254 results on '"Davies, Jonathan"'
Search Results
2. Structure-function studies on Clostridium botulinum neurotoxins
- Author
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Davies, Jonathan, Subramanian, Vasanta, and Acharya, K-Ravi
- Subjects
570 - Abstract
Botulinum neurotoxins (BoNTs) are the deadliest proteins known and cause flacid paralysis through inhibition of acetylcholine release from motor neurons. Each BoNT consists of three domains: the binding domain, the translocation domain and the catalytic light chain. The binding domain is responsible for the targetting of neuronal cell membranes and is able to form a dual-receptor complex with cell-surface receptors. The BoNT is taken into the cell through endocytosis where the translocation domain acts to release the catalytic light chain into the cell cytosol. The light chain is then free to cleave one of the SNARE (soluble N-ethylmaleimide-sensitive-fusion-protein attachment protein receptor) proteins, inhibiting exocytosis and thus neurotransmitter release. BoNTs are categorised into serotypes (BoNT/A to /G) and subtypes (e.g. BoNT/A1) based on amino acid variations. BoNTs have many therapeutic uses including as a treatment for cervical dytonia, strabismus, and overactive bladder and the most common commercially available product consists of BoNT/A1. Subtle amino acid variations between BoNT subtypes may have a dramatic impact on the properties of the protein, some of which may be useful for the production of engineered BoNTs in the future. In this thesis, the crystal structures of the binding domains from BoNT/A1 to /A6 were determined to high resolution and their binding to the protein-receptor SV2 was investigated. The structures of full-length BoNTs in solution were also investigated to confirm whether multiple domain-organisations exist across BoNT serotypes. There are over 150 different BoNTs known and this work also includes a new open-access tool for identifying and retrieving information about specific BoNTs in a fast and easy way.
- Published
- 2019
3. The role of mesenchymal cells in the regeneration of salivary gland tissue
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Davies, Jonathan Paul
- Subjects
616.3 ,Salivary Glands ,Sjogren's Syndrome ,Stem Cells ,Oral and Dental Sciences ,Tissue Regeneration ,Organoid Models ,Molecular Biology ,Mesenchymal Cells ,Epithelial Cells - Abstract
Primary Sjogren's Syndrome (PSS) patients will suffer a variable degree of damage to their salivary glands, caused by lesions of immune infiltrates into the tissue surrounding duct structures. Some patients present with extensive lesions that destroy any residual secretory acinar tissue, leading to hyposalivation. This damage, and reduced salivation, can lead to deleterious effects on the oral health, such as increased risk of caries and periodontitis, and will impact the general quality of life of the patients and can increase their risk of developing other, more serious conditions. Previously, there has been limited knowledge and characterisation of how different cell populations are impacted by PSS. Therefore, this project developed clear characterisation of labial salivary gland tissue from patients presenting with PSS compared to non-PSS patient samples. It was shown that regions that were not directly associated to lesions present with the same phenotypical profile as observed in non-PSS patients, indicating a very limited focal impact of the disorder. These regions stained positively for E-cadherin and Vimentin in patterns that were comparable to non-PSS patient samples. Simultaneously, the directly affected lesion regions presented with complete absence of any healthy salivary gland cell markers. Peri-lesion tissue presented with subtle changes to marker expression; here we could identify changes to mesenchymal cell markers such as PDGFRb and CD29 between the PSS and non-PSS tissue. The established immunofluorescent markers could further be used in later experimentations to identify each cell population, particularly when developing cell cultures and organoid models. 23 In order to investigate the impact of PSS on the ability of cells to proliferate and perform a rudimentary regenerative function, the group developed cell cultures that were representative of epithelial and mesenchymal cell types and recombined them to form organoid models. These models were first developed using mouse derived cell cultures before being adapted for use with human derived cells. Using these organoid models, it was possible to demonstrate that mesenchymal cells isolated from PSS positive patients had a reduced ability to direct the regenerative capacity of the epithelial spheroid structures, resulting in smaller, less complex, and less functionally advanced organoids than those developed using non-PSS derived cells. During this study, standard techniques were used such as quantitative real-time PCR of relative mRNA expression levels, immunofluorescent staining, and laser capture microdissection (LCM), whilst a novel organoid culture technique was optimised. Since these models have been established, it is thought that they could be adapted to investigate other disease or environmental impact on the salivary gland tissue, with some preliminary studies attempting to investigate the impact of x-ray irradiation exposure on the tissue. Furthermore, the technique could possibly be extrapolated to other tissue types to aid the understanding of the effect of other autoimmune conditions on their target tissues. In conclusion, this project shows mesenchymal cells appear to play an important and necessary role within tissue regeneration models. There is a significant change to cell fate determination pathways in PSS positive patient biopsies, and these mechanistic changes now need to be studied further within the constraints of the organoid model that has been developed.
- Published
- 2019
4. Migrant labour exploitation and harm in UK food supply chains
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Davies, Jonathan and Medina-Ariza, Juan
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340 ,Harm ,Labour exploitation ,Migrant workers ,Food supply chains - Abstract
The research conducted for this thesis is an exploratory study of migrant workers' experiences in UK food supply chains. This thesis provides an original contribution to criminology by discussing how some food supply chain dynamics result in various exploitative and harmful labour practices against migrant workers. Data consisted of semi-structured interviews conducted with migrant workers in the UK, as well as individual and group interviews with food supply chain stakeholders, including representatives from industry, regulation, and labour movements. This research conceptualises labour exploitation as a continuum, with severe practices including modern slavery on one extreme and 'decent work' on the other. There are a range of practices in-between these two extremes that risk being overlooked, whereby 'routine', banal exploitation is embedded and normalised within legitimate supply chain processes. The argument developed in this thesis is that a stronger emphasis is needed on the harmful consequences of routine, mundane, everyday labour exploitation in order to understand how they can result from legitimate supply chain dynamics. The key contributions of this thesis can be summarised under four themes: developing a more rigorous analysis of 'routine' labour exploitation and harm against migrant workers; understanding how legitimate food supply chain dynamics can facilitate exploitation and harm; explaining how the regulatory framework may unwittingly result in further exploitation and harm to migrant workers; and recognising the complexity of the relationship between migration and labour exploitation. The thesis findings contribute to predominant discussions of labour exploitation that typically focus on severe exploitation such as modern slavery and emphasise rogue individuals or criminal networks as the main perpetrators. The research findings demonstrate that a significant amount of routine labour exploitation and harm remains 'under the radar' in the context of legitimate supply chain practices. Police action and supply chain regulation typically focuses on the most severe labour exploitation, which results in routine exploitation being largely unaddressed. Therefore, labour exploitation has implications for the nature, organisation, and control of harms facilitated by businesses and supply chains. It is important for criminology and society to not disregard routine labour exploitation, as these practices can result in numerous harmful consequences for workers. Since the public profile of labour exploitation continues to grow, a stronger focus is needed on the routine and banal aspects, not just the most severe practices.
- Published
- 2018
5. New Developments in Urban Governance: Rethinking Collaboration in the Age of Austerity
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Davies, Jonathan S., Blanco, Ismael, Bua, Adrian, Chorianopoulos, Ioannis, Cortina-Oriol, Mercè, Feandeiro, Andrés, Gaynor, Niamh, Gleeson, Brendan, Griggs, Steven, Hamel, Pierre, Henderson, Hayley, Howarth, David, Keil, Roger, Pill, Madeleine, Salazar, Yunailis, and Sullivan, Helen
- Published
- 2022
- Full Text
- View/download PDF
6. Sparse regression methods with measurement-error for magnetoencephalography
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Davies, Jonathan
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616.8 ,QA276 Mathematical statistics - Abstract
Magnetoencephalography (MEG) is a neuroimaging method for mapping brain activity based on magnetic field recordings. The inverse problem associated with MEG is severely ill-posed and is complicated by the presence of high collinearity in the forward (leadfield) matrix. This means that accurate source localisation can be challenging. The most commonly used methods for solving the MEG problem do not employ sparsity to help reduce the dimensions of the problem. In this thesis we review a number of the sparse regression methods that are widely used in statistics, as well as some more recent methods, and assess their performance in the context of MEG data. Due to the complexity of the forward model in MEG, the presence of measurement-error in the leadfield matrix can create issues in the spatial resolution of the data. Therefore we investigate the impact of measurement-error on sparse regression methods as well as how we can correct for it. We adapt the conditional score and simulation extrapolation (SIMEX) methods for use with sparse regression methods and build on an existing corrected lasso method to cover the elastic net penalty. These methods are demonstrated using a number of simulations for different types of measurement-error and are also tested with real MEG data. The measurement-error methods perform well in simulations, including high dimensional examples, where they are able to correct for attenuation bias in the true covariates. However the extent of their correction is much more restricted in the more complex MEG data where covariates are highly correlated and there is uncertainty over the distribution of the error.
- Published
- 2017
7. Representing the dynasty in Flavian Rome : the case of Josephus' "Jewish War"
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Davies, Jonathan and Goodman, Martin
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930 ,History ,Ancient ,Jewish Studies ,Classics ,Josephus ,Flavian dynasty ,Roman historiography - Abstract
This thesis investigates the problem of contemporary historiography and regime representation in Flavian Rome through a close study of a text not usually read for such purposes but which has obvious promise for a study of this theme, the Jewish War of Flavius Josephus. Having surveyed the evolution of our conception of Josephus' relationship to Flavian power, taken a broad account of issues of political expression and regime representation in Flavian Rome outside Josephus and examined questions relating to the structure and date of the work, I will provide a series of thematically-focused readings of the three senior members of the Flavian family, Vespasian, Titus and Domitian, as represented by their contemporary and client Josephus. Key topics to be explored include the level of independence of Josephus' vision, his work's relationship to how the regime is depicted in other contemporary sources, how Josephus makes the Flavians serve his own agenda (which is distinct from the heavy focus of most previous scholarship on how Josephus served their agenda), and the viability and usefulness of certain types of reading practices relating to figured critique which have recently become influential in Josephan scholarship. The thesis offers a new approach to Josephus' relationship to the Flavian Dynasty and sheds new light on contemporary historiography and political expression in the Early Principate.
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- 2017
8. Characterisation of the reversible formate dehydrogenases of Shewanella
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Davies, Jonathan A.
- Subjects
570 - Abstract
The reversible action of tungsten or molybdenum-containing formate dehydrogenase (FDH) enzymes in reducing CO2 to formate has been proposed for storing renewably produced electricity with concomitant CO2 sequestration. Previous attempts have highlighted the unfeasibility of using purified enzyme systems for biotechnological purposes. In response the possibility of using the exoelectrogenic bacteria Shewanella oneidensis in association with a cathode to drive intracellular CO2 reduction is proposed. Since the native FDH enzymes of S.oneidensis have not been previously studied, this work concerns their characterisation and directionality to inform both on native physiology and possible future biotechnological applications. This thesis demonstrates that the native FDH enzymes of S.oneidensis are capable of CO2 reductase activity. Both forward (Km 39 μM) and reverse (Km 1.43 mM) directions of FDH catalysis in whole cell cultures are maximal when cultured in the presence of W. When grown under such conditions, two FDH isoforms (Fdh1αβγ and Fdh2αβγ) contribute to these activities, with protein purification confirming Fdh2αβγ as a tungstoenzyme. CO2 reductase activity in S.oneidensis cultures could be driven by a cathode in simple three electrode electrochemical experiments without exogenous mediators with high coloumbic efficiency, representing an interesting paradigm for future inexpensive microbial electrosynthetic study.
- Published
- 2017
9. Kinetic study of shock formation and particle acceleration in laser-driven quasi-parallel magnetized collisionless shocks
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Zhang, Yu, Zhang, Yu, Heuer, Peter V, Davies, Jonathan R, Schaeffer, Derek B, Wen, Han, García-Rubio, Fernando, Ren, Chuang, Zhang, Yu, Zhang, Yu, Heuer, Peter V, Davies, Jonathan R, Schaeffer, Derek B, Wen, Han, García-Rubio, Fernando, and Ren, Chuang
- Published
- 2024
10. Evaluating the Introduction of the Digital Intervention Patient Participation Booking within Cardiff and Vale University Health Board
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Davies, Jonathan and Davies, Jonathan
- Abstract
Following the pandemic, outpatient waiting lists within Wales have risen significantly (Welsh Government, 2023a). Patients are waiting longer than ever before to receive treatment (Welsh Government, 2023a). To tackle waiting list (WL) issues, one solution proposed by Cardiff and Vale University Health Board (C&VUHB) is Patient Participation Booking (PPB). Evaluation will occur on how successful PPB is in achieving its aim of decreasing the Did Not Attend (DNA) rate for new acute outpatient appointments (NAOA) within C&VUHB. PPB’s success in lowering the demand on administrative services will also be a particular focus, along with improving patient communication.
- Published
- 2024
11. Reappraisal of SU(3)-flavor breaking in $B\rightarrow DP$
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Davies, Jonathan, Schacht, Stefan, Skidmore, Nicola, Soni, Amarjit, Davies, Jonathan, Schacht, Stefan, Skidmore, Nicola, and Soni, Amarjit
- Abstract
In light of recently found deviations of the experimental data from predictions from QCD factorization for $B_{(s)}\rightarrow D_{(s)}P$ decays, where $P=\{\pi,K\}$, we systematically probe the current status of the SU(3)$_F$ expansion from a fit to experimental branching ratio data without any further theory input. We find that the current data is in agreement with the power-counting of the SU(3)$_F$ expansion. While the SU(3)$_F$ limit is excluded at $>5\sigma$, SU(3)$_F$-breaking contributions of $\sim 20\%$ suffice for an excellent description of the data. SU(3)$_F$ breaking is needed in tree ($>5\sigma$) and color-suppressed tree ($2.4\sigma$) diagrams. We are not yet sensitive to SU(3)$_F$ breaking in exchange diagrams. From the underlying SU(3)$_F$ parametrization we predict the unmeasured branching ratios $\mathcal{B}(\overline{B}_s^0\rightarrow \pi^- D^+) = 2 \mathcal{B}(\overline{B}_s^0\rightarrow \pi^0 D^0) = [0.3, 7.2] \times 10^{-6}$ of suppressed decays that can be searched for at the LHCb Upgrade I and LHCb Upgrade II experiments respectively., Comment: 7 pages
- Published
- 2024
12. Exploring the inherent conflict between the internationalisation and carbon management agendas in the UK higher education sector
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Davies, Jonathan Christopher
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378.1 - Abstract
Globally, higher education institutions (HEIs) can help facilitate the transition to a low-carbon society through their role as educators, researchers and community leaders. Focusing on their role as educators, one of the central concepts of education for sustainable development is global citizenship, where for UK HEIs the recruitment of international students and study abroad schemes have been a fundamental way of encouraging home students to develop global perspectives. However, this approach conflicts with the sector's low-carbon agenda due to the significant emissions from air travel (hereafter 'the Conflict'). To evaluate the scale of student air travel emissions, and to explore students and HEIs awareness of, and willingness to mitigate and/or compensate for these emissions, this study adopted a convergent and integrated parallel strand mixed methods design. This comprised of a cross-sectional survey of 663 international and study abroad students and document analysis and in-depth interviews under the umbrella of eight HEI case studies. An analysis of UK HE sector statistics, in combination with flight frequencies determined from the student survey, found that student air travel emissions were equivalent to 68% of estates emissions, or 119% when visiting friends and relatives were taken into account. Furthermore, scenario analysis suggested that by 2020/21, increases in these emissions are likely to exceed the reductions achieved in estates emissions unless HEIs reinvigorate efforts to achieve their ambitious reduction targets, and/or there is close to zero annual growth in inbound and outbound student numbers. The findings from the eight case studies revealed that the sector is poorly equipped to respond to the Conflict. This relates to an ongoing focus on, and difficulties achieving, estates emission reductions, varied engagement with indirect (supply chain) emissions, and an unwillingness at the institutional level from the majority of HEIs to engage with the Conflict. To have credibility and be in a position to respond strategically to the Conflict, HEIs should include student air travel emissions in a comprehensive carbon footprint. Moreover, a robust carbon management strategy for the sector should include offsetting due to the limited potential to avoid or reduce these emissions through reduction in air travel consumption. This is evidenced by both responses to the student survey and the importance placed on student mobility by the HEIs. Clearly, there are challenges for organisations who face conflicting business priorities in responding to the carbon management agenda. Organisations need to account for and engage with indirect emission sources such as employee commuting and business travel, and the emissions associated with products (goods and services). The reluctance and inability to engage with challenges that require a trade-off, or compromise between socio-economic benefits and environmental costs has implications for the achievability of a global reduction in emissions.
- Published
- 2016
13. Between Realism and Revolt: Governing Cities in the Crisis of Neoliberal Globalism
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Davies, Jonathan S.
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- 2021
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14. Motion perception following simultaneous adaptation to smooth pursuit eye movement and retinal motion
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Davies, Jonathan Rhys
- Subjects
152.14 - Abstract
This study employed adaptation paradigms to explore visual motion processing during smooth pursuit eye movement. Two classes of model, classical models and reference signal models, employ estimates of retinal motion and pursuit to estimate head-centred world motion. The pursuit estimate in classical models is purely extra-retinal. In reference signal models the pursuit estimate is additionally modulated by retinal feedback. Chapters 2 and 3 investigated the motion aftereffect (MAE) following adaptation to simultaneous retinal motion and smooth pursuit. In chapter 2 adaptations to either horizontal retinal motion or vertical smooth pursuit respectively resulted in retinal or extra-retinal MAE. Simultaneous orthogonal adaptation to both motions resulted in a unidirectional MAE that bisected the individual MAE directions. Adaptation to a head-centred motion signal (perceived direction) was not supported by the recorded directions for adapting motion and resulting MAE. An explanation employing separate lower level adaptations was favoured. Chapters 3 and 4 examined motion perception following collinear motion adaptation. Additionally, the retinotopic nature of retinal motion adaptation was exploited to limit the effects of retinal sensor adaptation during the test phase. The two classes of model then make differing predictions: Reference signal models predict a pursuit estimate that is modulated by retinal motion, whilst classical models do not. In chapter 3 varying the background motion during adaptation did alter the physical eye movement. However, the properties of the resulting MAE were not modulated by retinal feedback and a classical model was supported. Chapter 4 used a moving test to quantify the perceived stability of a background during smooth pursuit using a two alternative forced choice paradigm and staircase procedure. Either a phantom velocity aftereffect or a modified reference signal model was suggested as modulating the Filehne illusion in Experiment 6. Two control experiments failed to find evidence for phantom adaptation. Experiment 9 demonstrated a potential retinotopic location bias for background motion when applying a reference signal model, background motion above the test area did not alter perceived stability judgments.
- Published
- 2010
15. Epistemologies and ontologies of genomics : two approaches to the problems of biology
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Davies, Jonathan
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570.1 - Abstract
If we were to ask the question, "why does organism X develop/behave as it does?" or, "why does organism X give rise (through e.g. sexual reproduction) to an organism that is similar to itself?" we have two broad types of explanation: the localised and the distributed. These, and other questions addressed in developmental and evolutionary biology, I characterise as problems of biology. Localised causal explanations (LCEs) focus on the identification of an entity (localised in space) or event (localised in time) responsible for the phenomenon to be explained. Distributed causal explanations (DCEs) have tended to focus on the identification of (often global) properties or features (distributed in space) or processes (distributed in time) responsible for the phenomenon to be explained.
- Published
- 2009
16. The developmental precursors of episodic memory
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Davies, Jonathan Gareth Gwyn
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155 - Abstract
Converging evidence suggests that it is not until the age of approximately 4 years that children can mentally time-travel back in time to re-experience episodes from their life (‘episodic memory’). This research was motivated by two questions: (1) how does episodic-like memory emerge out of event memory? And (2) to what extend does episodic-like memory share some of the psychological characteristics of episodic memory (e.g. the putative dependence on grasping the representing relationship between knowledge and experience, as demonstrated by tests of seeing-leads-to-knowing)? Three tasks were conducted to address these issues. The first, the ‘two-object what & where’ task employed an object-placement/witnessed pilfer design, and found that shortly after the second birthday children become able to integrate ‘what’ information (with respect to objects) in day-long location memory. In the ‘Tim and Tom’ task, deferred imitation of a two-step action sequence was used to demonstrate the presence of day-long event memory in children upwards of 36-months-of-age. Finally, the ‘what, where, when’ task tested for the presence of episodic-like memory in 3- to 4-year-olds, and established that children found conditions which require them to remember how long ago an event had happened were significantly harder than conditions without this requirement. The abilities tested by the ‘what, where, when’ task were not found to recruit theory-of-mind or seeing-leads-to-knowing abilities. Given this, the ‘what, where, when’ task can be interpreted as supporting the distinction drawn between episodic and episodic-like memory.
- Published
- 2007
17. The role of livestock in Afar pastoral livelihoods : capitalisation, commoditisation and obligation
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Davies, Jonathan M.
- Subjects
338.140963 - Published
- 2003
18. An exploration of the challenges facing CEOs of privatised utilities and their response to those challenges in terms of actions and leadership style
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Davies, Jonathan
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658 ,Usability evaluation methods - Published
- 2003
19. Underwater acoustic communications
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Davies, Jonathan James
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620 ,Acoustics & noise analysis - Published
- 2002
20. U.H.V. electrochemical transfer studies of modified platinum single crystal surfaces : models for fuel cell catalysis
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Davies, Jonathan Conrad
- Subjects
541 ,Physical chemistry - Abstract
Adsorbed and incorporated ruthenium on Pt(110) has been probed using the techniques of LEISS, LEED and XPS. Well characterised alloy surfaces have been prepared by annealing in the temperature range 400-1100K and the temperature programmed desorption of CO investigated. Second layer ruthenium is shown to have a major effect on the adsorption characteristics of CO. The catalytic activity of these surfaces towards the electro-oxidation of CO has been determined using cyclic voltammetry. The reversible hydrogen adsorption peaks are perturbed by subsurface ruthenium, however, promotion of the electro-oxidation of CO, as evidenced by a downwards potential shift, occurs solely due to ruthenium incorporated into the top atomic layer. The adsorption of ruthenium on Pt(111) has been investigated by LEISS, XPS and LEED. At room temperature clusters of ruthenium are obtained. On annealing competition occurs between the processes of spreading of these clusters and incorporation of ruthenium into the Pt(111) surface. Two Clavilier bead crystals have been prepared of the Pt(111) and Pt(533) surfaces. Promotion of the electro-oxidation of CO by ruthenium spontaneously deposited onto these surfaces from a RuCl₃ solution, before and after reduction of the surface ruthenium species, has been demonstrated. A particularly sharp oxidation peak at 0.53 V is observed on the Pt(533) - Ru system after exposure to hydrogen, attributed to the formation of an ideal "alloy" ensemble at the step.
- Published
- 1999
21. Urban regime theory in critical perspective : a comparative study of public-private partnerships in UK local governance
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Davies, Jonathan Stephen
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320 ,Barnsley ,Rotherham ,Hull ,Lincolnshire - Published
- 1999
22. Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1
- Author
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Wallner, Olov, Cázares-Körner, Armando, Scaletti, Emma Rose, Masuyer, Geoffrey, Bekkhus, Tove, Visnes, Torkild, Mamonov, Kirill, Ortis, Florian, Lundbäck, Thomas, Volkova, Maria, Koolmeister, Tobias, Wiita, Elisée, Loseva, Olga, Pandey, Monica, Homan, Evert, Benítez-Buelga, Carlos, Davies, Jonathan, Scobie, Martin, Warpman Berglund, Ulrika, Kalderén, Christina, Stenmark, Pål, Helleday, Thomas, Michel, Maurice, Wallner, Olov, Cázares-Körner, Armando, Scaletti, Emma Rose, Masuyer, Geoffrey, Bekkhus, Tove, Visnes, Torkild, Mamonov, Kirill, Ortis, Florian, Lundbäck, Thomas, Volkova, Maria, Koolmeister, Tobias, Wiita, Elisée, Loseva, Olga, Pandey, Monica, Homan, Evert, Benítez-Buelga, Carlos, Davies, Jonathan, Scobie, Martin, Warpman Berglund, Ulrika, Kalderén, Christina, Stenmark, Pål, Helleday, Thomas, and Michel, Maurice
- Abstract
8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8-oxoG could lead to G : C→T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on results from a small molecule screening campaign, we performed hit to lead expansion and arrived at potent and selective substituted N-piperidinyl-benzimidazolones. Using X-ray crystallography data, we describe the surprising binding mode of the most potent member of the class, TH8535. Here, the N-Piperidinyl-linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target engagement and efficacy of TH8535 against a number of cancer cell lines.
- Published
- 2023
- Full Text
- View/download PDF
23. $\bar{B}\rightarrow \bar{D} D$ Decays and the Extraction of $f_d/f_u$ at Hadron Colliders
- Author
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Davies, Jonathan, Jung, Martin, Schacht, Stefan, Davies, Jonathan, Jung, Martin, and Schacht, Stefan
- Abstract
We perform a detailed model-independent phenomenological analysis of $\bar B\to \bar D D$ decays. Employing an SU(3)$_F$ analysis including symmetry-breaking contributions together with a conservative power counting for various suppression effects, we obtain updated Standard Model predictions for all branching fractions and CP asymmetries from a fit to the available experimental data, testable at Belle II and the LHC experiments. These results include all relevant suppressed contributions, thereby providing upper limits on subleading Standard Model (SM) effects like "penguin pollution", enabling searches for physics beyond the SM. Importantly, allowing in the same fit for the production fractions of charged and neutral $B$ mesons to be different, we find $f_d/f_u = 0.86\pm0.05$, which is $2.5\sigma$ away from unity, which, if confirmed, would have important phenomenological consequences., Comment: 24 pages. Matches published version
- Published
- 2023
24. Are the fates of supermassive black holes and galaxies determined by individual mergers, or by the properties of their host haloes?
- Author
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Davies, Jonathan J., Pontzen, Andrew, Crain, Robert A., Davies, Jonathan J., Pontzen, Andrew, and Crain, Robert A.
- Abstract
The fates of massive galaxies are tied to the evolution of their central supermassive black holes (BHs), due to the influence of AGN feedback. Correlations within simulated galaxy populations suggest that the masses of BHs are governed by properties of their host dark matter haloes, such as the binding energy and assembly time, at a given halo mass. However, the full picture must be more complex as galaxy mergers have also been shown to influence the growth of BHs and the impact of AGN. In this study, we investigate this problem through a controlled experiment, using the genetic modification technique to adjust the assembly history of a Milky Way-like galaxy simulated with the EAGLE model. We change the halo assembly time (and hence the binding energy) in the absence of any disruptive merger events, and find little change in the integrated growth of the BH. We attribute this to the angular momentum support provided by a galaxy disc, which reduces the inflow of gas towards the BH and effectively decouples the BH's growth from the halo's properties. Introducing major mergers into the assembly history disrupts the disc, causing the BH to grow $\approx 4\times$ more massive and inject feedback that reduces the halo baryon fraction by a factor of $\approx 2$ and quenches star formation. Merger events appear essential to the diversity in BH masses in EAGLE, and we also show that they increase the halo binding energy; correlations between these quantities may therefore be the result of merger events., Comment: 12 pages, 5 figures. Accepted for publication in MNRAS
- Published
- 2023
25. Propagation of radio signals into and within multi-storey buildings at 900 MHz and 1800 MHz
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Davies, Jonathan Gary
- Subjects
621.382 ,Mobile radio channels ,Narrowband ,Wideband - Published
- 1997
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26. Aspects of the life history and physiological ecology of long-lived nudibranch molluscs
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Davies, Jonathan and Todd, Christopher David
- Subjects
594 ,QL430.5D2 ,Mollusks - Abstract
Nudibranchia is the major Order of the gastropod Sub-class Opisthobranchia. Nudibranchs demonstrate a considerable evolutionary departure from the typical shelled gastropod and have achieved wide morphological and ecological diversity. Most species are recorded from nearshore rocky habitats where they are primary macrobenthic predators; most species are stenophagous limited to a single, or a few, prey species. Previous investigations had shown that most nudibranch species have evolved to an annual semelparous life history strategy and adopt a planktotrophic larval development strategy which would appear to be the ancestral conditions. Reviews of published data had drawn attention to some species which demonstrated an evolutionary departure from these ancestral modes and had evolved extended life history strategies combined with more advanced larval development strategies. Archidoris pseudoargus and Cadlina laevis are sponge-grazing dorid nudibranchs, and Tritonia hombergi, which feeds on an alyconarean soft coral, appeared to have extended life cycles. The aim of the present study was to investigate the life history and larval development strategies of these species and, via a study their physiological ecology, attempt to determine the selective forces which may have driven any evolutionary departure away from the ancestral condition. Archidoris pseudoargus was found to have a biennial semelparous life history strategy and a planktotrophic larval development strategy; the planktotrophic lai'vae were found to have some characteristics of the more advanced lecithotrophic laeval form. Cadlina laevis was found to have a perennial iteropalous life history strategy and a direct mode of larval development; this was the first observation of perennial iteroparity in the Order Nudibranchia. Archidoris pseudoargus and Cadlina laevis had markedly seasonal growth patterns with a high growth rate in spring and early summer, followed by a period of reduced growth, or even degrowth in late summer and over the winter. An allometric relationship was determined between body size and feeding rate for A. pseudoargus; the exponent was less than unity. For both species, a significant allometric relationship was determined between body size and respiration rate with an exponent less than unity indicating an increase in metabolic efficiency with body size. Both species displayed an acclimatization of respiration rate with increasing temperature; the acclimatization was more pronounced in C. laevis. Fecundity of both species was shown to have a significant allometric relationship body size with an exponent less than unity. Insufficient numbers of T. hombergi were collected and kept alive in the laboratory to undertake any experiments to generate meaningful data to answer these principal questions for this species. Results of the present study together with data published from previous investigations have been interpreted to suggest that the extension of the life cycle is a consequence of seasonal variations in prey quality and quantity. Rather than being an exception to the rule, it is suggested that extended life cycles could be the ancestral condition and the more common annual/sub annual life cycles would be a more adapted condition. These conclusions are based on the results obtained from laboratory investigations which are discussed in their application to the field situation.
- Published
- 1993
27. The Studio Fiorentino, 1385-1473
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Davies, Jonathan Douglas
- Subjects
900 ,History - Published
- 1992
28. Structural and computational studies of herbicides active via photosystem II
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Davies, Jonathan Michael Richard
- Subjects
631.8 ,Agricultural chemistry & fertilizers - Abstract
This Thesis aims to increase the understanding of the way in which herbicides inhibit plant photosynthesis by interference at the site of photosystem II. Two structurally dissimilar series of compounds, provided by Schering Agrochemicals (Saffron Walden, U.K.), one rigid, one flexible, both series showing varying herbicidal activity, were submitted to X-ray crystallography, NMR spectroscopy and molecular modelling studies. As a result of these investigations, an explanation is given for the observed trend in activity of both series of compounds. A template for the herbicide binding site is also presented. The most active molecules in the two series of' compounds were compared using molecular modelling. A model is presented which suggests that both molecules may interact with the same binding site at the photosystem II reaction centre.
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- 1991
29. Galaxy mergers can initiate quenching by unlocking an AGN-driven transformation of the baryon cycle
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Davies, Jonathan J., Pontzen, Andrew, Crain, Robert A., Davies, Jonathan J., Pontzen, Andrew, and Crain, Robert A.
- Abstract
We use zoom simulations to show how merger-driven disruption of the gas disc in a galaxy provides its central active galactic nucleus (AGN) with fuel to drive outflows that entrain and expel a significant fraction of the circumgalactic medium (CGM). This in turn suppresses replenishment of the interstellar medium, causing the galaxy to quench up to several Gyr after the merger. We start by performing a zoom simulation of a present-day star-forming disc galaxy with the EAGLE galaxy formation model. Then, we re-simulate the galaxy with controlled changes to its initial conditions, using the genetic modification technique. These modifications either increase or decrease the stellar mass ratio of the galaxy's last significant merger, which occurs at $z\approx 0.74$. The halo reaches the same present-day mass in all cases, but changing the mass ratio of the merger yields markedly different galaxy and CGM properties. We find that a merger can unlock rapid growth of the central supermassive black hole if it disrupts the co-rotational motion of gas in the black hole's vicinity. Conversely, if a less disruptive merger occurs and gas close to the black hole is not disturbed, the AGN does not strongly affect the CGM, and consequently the galaxy continues to form stars. Our result illustrates how a unified view of AGN feedback, the baryon cycle and the interstellar medium is required to understand how mergers and quenching are connected over long timescales., Comment: 13 pages, 8 figures. Submitted to MNRAS, comments welcome
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- 2022
30. Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
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Michel, Maurice, Benitez-Buelga, Carlos, Calvo, Patricia A., Hanna, Bishoy M. F., Mortusewicz, Oliver, Masuyer, Geoffrey, Davies, Jonathan, Wallner, Olov, Sanjiv, Kumar, Albers, Julian J., Castaneda-Zegarra, Sergio, Jemth, Ann-Sofie, Visnes, Torkild, Sastre-Perona, Ana, Danda, Akhilesh N., Homan, Evert J., Marimuthu, Karthick, Zhenjun, Zhao, Chi, Celestine N., Sarno, Antonio, Wiita, Elisee, von Nicolai, Catharina, Komor, Anna J., Rajagopal, Varshni, Müller, Sarah, Hank, Emily C., Varga, Marek, Scaletti, Emma R., Pandey, Monica, Karsten, Stella, Haslene-Hox, Hanne, Loevenich, Simon, Marttila, Petra, Rasti, Azita, Mamonov, Kirill, Ortis, Florian, Schömberg, Fritz, Loseva, Olga, Stewart, Josephine, D'Arcy-Evans, Nicholas, Koolmeister, Tobias, Henriksson, Martin, Michel, Dana, de Ory, Ana, Acero, Lucia, Calvete, Oriol, Scobie, Martin, Hertweck, Christian, Vilotijevic, Ivan, Kalderen, Christina, Osorio, Ana, Perona, Rosario, Stolz, Alexandra, Stenmark, Pål, Berglund, Ulrika Warpman, de Vega, Miguel, Helleday, Thomas, Michel, Maurice, Benitez-Buelga, Carlos, Calvo, Patricia A., Hanna, Bishoy M. F., Mortusewicz, Oliver, Masuyer, Geoffrey, Davies, Jonathan, Wallner, Olov, Sanjiv, Kumar, Albers, Julian J., Castaneda-Zegarra, Sergio, Jemth, Ann-Sofie, Visnes, Torkild, Sastre-Perona, Ana, Danda, Akhilesh N., Homan, Evert J., Marimuthu, Karthick, Zhenjun, Zhao, Chi, Celestine N., Sarno, Antonio, Wiita, Elisee, von Nicolai, Catharina, Komor, Anna J., Rajagopal, Varshni, Müller, Sarah, Hank, Emily C., Varga, Marek, Scaletti, Emma R., Pandey, Monica, Karsten, Stella, Haslene-Hox, Hanne, Loevenich, Simon, Marttila, Petra, Rasti, Azita, Mamonov, Kirill, Ortis, Florian, Schömberg, Fritz, Loseva, Olga, Stewart, Josephine, D'Arcy-Evans, Nicholas, Koolmeister, Tobias, Henriksson, Martin, Michel, Dana, de Ory, Ana, Acero, Lucia, Calvete, Oriol, Scobie, Martin, Hertweck, Christian, Vilotijevic, Ivan, Kalderen, Christina, Osorio, Ana, Perona, Rosario, Stolz, Alexandra, Stenmark, Pål, Berglund, Ulrika Warpman, de Vega, Miguel, and Helleday, Thomas
- Abstract
Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed beta,delta-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.
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- 2022
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31. Structural Analysis of Botulinum Neurotoxins Type B and E by Cryo-EM
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Kosenina, Sara, Martínez-Carranza, Markel, Davies, Jonathan R., Masuyer, Geoffrey, Stenmark, Pål, Kosenina, Sara, Martínez-Carranza, Markel, Davies, Jonathan R., Masuyer, Geoffrey, and Stenmark, Pål
- Abstract
Botulinum neurotoxins (BoNTs) are the causative agents of a potentially lethal paralytic disease targeting cholinergic nerve terminals. Multiple BoNT serotypes exist, with types A, B and E being the main cause of human botulism. Their extreme toxicity has been exploited for cosmetic and therapeutic uses to treat a wide range of neuromuscular disorders. Although naturally occurring BoNT types share a common end effect, their activity varies significantly based on the neuronal cell-surface receptors and intracellular SNARE substrates they target. These properties are the result of structural variations that have traditionally been studied using biophysical methods such as X-ray crystallography. Here, we determined the first structures of botulinum neurotoxins using single-particle cryogenic electron microscopy. The maps obtained at 3.6 and 3.7 Å for BoNT/B and /E, respectively, highlight the subtle structural dynamism between domains, and of the binding domain in particular. This study demonstrates how the recent advances made in the field of single-particle electron microscopy can be applied to bacterial toxins of clinical relevance and the botulinum neurotoxin family in particular.
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- 2022
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32. Embedding digital participatory budgeting within local government: motivations, strategies and barriers faced
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Davies, Jonathan, Arana-Catania, Miguel, Procter, Rob, Davies, Jonathan, Arana-Catania, Miguel, and Procter, Rob
- Abstract
The challenging task of embedding innovative participatory processes and technologies within local government often falls upon local council officers. Using qualitative data collection and analysis, we investigate the ongoing work of Scottish local councils seeking to run the process of participatory budgeting (PB) within their institution, the use of digital platforms to support this and the challenges faced. In doing so this paper draws on empirical material to support the growing discussion on the dynamics or forces behind embedding. Our analysis shows that formal agreement alone does not make the process a certainty. Local council officers must work as mediators in the transitional space between representative structures and new, innovative ways of working, unsettling the entrenched power dynamics. To do so they must be well trained and well resourced, including the ability to use digital platforms effectively as part of the process. This provides the necessary, accessible, transparent and deliberative space for participation., Comment: 12 pages, presented at the 15th International Conference on Theory and Practice of Electronic Governance 2022
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- 2022
33. DNA methylation signatures of Alzheimer's disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types
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Shireby, Gemma, Dempster, Emma L, Policicchio, Stefania, Smith, Rebecca G, Pishva, Ehsan, Chioza, Barry, Davies, Jonathan P, Burrage, Joe, Lunnon, Katie, Seiler Vellame, Dorothea, Love, Seth, Thomas, Alan, Brookes, Keeley, Morgan, Kevin, Francis, Paul, Hannon, Eilis, Mill, Jonathan, Shireby, Gemma, Dempster, Emma L, Policicchio, Stefania, Smith, Rebecca G, Pishva, Ehsan, Chioza, Barry, Davies, Jonathan P, Burrage, Joe, Lunnon, Katie, Seiler Vellame, Dorothea, Love, Seth, Thomas, Alan, Brookes, Keeley, Morgan, Kevin, Francis, Paul, Hannon, Eilis, and Mill, Jonathan
- Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n = 2013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at loci not previously implicated in dementia. We subsequently profiled DNA methylation in NeuN+ (neuronal-enriched), SOX10+ (oligodendrocyte-enriched) and NeuN-/SOX10- (microglia- and astrocyte-enriched) nuclei, finding that the majority of DMPs identified in 'bulk' cortex tissue reflect DNA methylation differences occurring in non-neuronal cells. Our study highlights the power of utilizing multiple measures of neuropathology to identify epigenetic signatures of AD and the importance of characterizing disease-associated variation in purified cell-types.
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- 2022
34. Environmental effects in Herschel observations of the ionized carbon content of star forming dwarf galaxies in the Virgo cluster
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Minchin, Robert, Fadda, Dario, Taylor, Rhys, Deshev, Boris, Davies, Jonathan, Minchin, Robert, Fadda, Dario, Taylor, Rhys, Deshev, Boris, and Davies, Jonathan
- Abstract
We use archival Herschel data to examine the singly ionized carbon ([CII]) content of 14 star forming dwarf galaxies in the Virgo cluster. We use spectral energy distribution (SED) fits to far infrared, mid infrared, near infrared, optical and ultraviolet data to derive the total infrared continuum (TIR) for these galaxies. We compare the [CII]/TIR ratio for dwarf galaxies in the central part of Virgo to those in the southern part of the cluster and to galaxies with similar TIR luminosities and metallicities in the Herschel Dwarf Galaxy Survey (DGS) sample of field dwarf galaxies to look for signs of [CII] formation independent of star formation. Our analysis indicates that the sample of Virgo dwarfs in the central part of the cluster has significantly higher values of [CII]/TIR than the sample from the southern part of the cluster and the sample from the DGS, while the southern sample is consistent with the DGS. This [CII]/TIR excess implies that a significant fraction of the [CII] in the dwarf galaxies in the cluster center has an origin other than star formation and is likely to be due to environmental processes in the central part of the cluster. We also find a surprisingly strong correlation between [CII]/TIR and the local ram pressure felt by the dwarf galaxies in the cluster. In this respect, we claim that the excess [CII] we see in these galaxies is likely to be due to formation in ram pressure shocks., Comment: 20 pages, accepted for publication in the Astronomical Journal
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- 2022
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35. Challenging Governance Theory: From Networks to Hegemony
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Davies, Jonathan S.
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- 2011
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36. Predictions for the X-ray circumgalactic medium of edge-on discs and spheroids
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Nica, Anna, Oppenheimer, Benjamin D., Crain, Robert A., Bogdán, Ákos, Davies, Jonathan J., Forman, William R., Kraft, Ralph P., ZuHone, John A., Nica, Anna, Oppenheimer, Benjamin D., Crain, Robert A., Bogdán, Ákos, Davies, Jonathan J., Forman, William R., Kraft, Ralph P., and ZuHone, John A.
- Abstract
We investigate how the X-ray circumgalactic medium (CGM) of present-day galaxies depends on galaxy morphology and azimuthal angle using mock observations generated from the EAGLE cosmological hydrodynamic simulation. By creating mock stacks of {\it eROSITA}-observed galaxies oriented to be edge-on, we make several observationally-testable predictions for galaxies in the stellar mass range $M_\star=10^{10.7-11.2}\;$M$_{\odot}$. The soft X-ray CGM of disc galaxies is between 60 and 100\% brighter along the semi-major axis compared to the semi-minor axis, between 10-30 kpc. This azimuthal dependence is a consequence of the hot ($T>10^6$ K) CGM being non-spherical: specifically it is flattened along the minor axis such that denser and more luminous gas resides in the disc plane and co-rotates with the galaxy. Outflows enrich and heat the CGM preferentially perpendicular to the disc, but we do not find an observationally-detectable signature along the semi-minor axis. Spheroidal galaxies have hotter CGMs than disc galaxies related to spheroids residing at higher halos masses, which may be measurable through hardness ratios spanning the $0.2-1.5$ keV band. While spheroids appear to have brighter CGMs than discs for the selected fixed $M_\star$ bin, this owes to spheroids having higher stellar and halo masses within that $M_\star$ bin, and obscures the fact that both simulated populations have similar total CGM luminosities at the exact same $M_\star$. Discs have brighter emission inside 20 kpc and more steeply declining profiles with radius than spheroids. We predict that the {\it eROSITA} 4-year all-sky survey should detect many of the signatures we predict here, although targeted follow-up observations of highly inclined nearby discs after the survey may be necessary to observe some of our azimuthally-dependent predictions., Comment: 12 pages, 11 figures, 1 table. Submitted to MNRAS. Comments welcome
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- 2021
37. COVID-19 crisis reduces free tropospheric ozone across the northern hemisphere
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Steinbrecht, Wolfgang, Kubistin, Dagmar, Plass-Dülmer, Christian, Davies, Jonathan, Tarasick, David W., von der Gathen, Peter, Deckelmann, Holger, Jepsen, Nis, Kivi, Rigel, Lyall, Norrie, Palm, Matthias, Notholt, Justus, Kois, Bogumil, Oelsner, Peter, Allaart, Marc, Piters, Ankie, Gill, Michael, Van Malderen, Roeland, Delcloo, Andy W., Sussmann, Ralf, Mahieu, Emmanuel, Servais, Christian, Romanens, Gonzague, Stübi, Rene, Ancellet, Gerard, Godin-Beekmann, Sophie, Yamanouchi, Shoma, Strong, Kimberly, Johnson, Bryan, Cullis, Patrick, Petropavlovskikh, Irina, Hannigan, James W., Hernandez, Jose-Luis, Rodriguez, Ana Diaz, Nakano, Tatsumi, Chouza, Fernando, Leblanc, Thierry, Torres, Carlos, Garcia, Omaira, Röhling, Amelie N., Schneider, Matthias, Blumenstock, Thomas, Tully, Matt, Paton-Walsh, Clare, Jones, Nicholas, Querel, Richard, Strahan, Susan, Stauffer, Ryan M., Thompson, Anne M., Inness, Antje, Engelen, Richard, Chang, Kai-Lan, Cooper, Owen R., Steinbrecht, Wolfgang, Kubistin, Dagmar, Plass-Dülmer, Christian, Davies, Jonathan, Tarasick, David W., von der Gathen, Peter, Deckelmann, Holger, Jepsen, Nis, Kivi, Rigel, Lyall, Norrie, Palm, Matthias, Notholt, Justus, Kois, Bogumil, Oelsner, Peter, Allaart, Marc, Piters, Ankie, Gill, Michael, Van Malderen, Roeland, Delcloo, Andy W., Sussmann, Ralf, Mahieu, Emmanuel, Servais, Christian, Romanens, Gonzague, Stübi, Rene, Ancellet, Gerard, Godin-Beekmann, Sophie, Yamanouchi, Shoma, Strong, Kimberly, Johnson, Bryan, Cullis, Patrick, Petropavlovskikh, Irina, Hannigan, James W., Hernandez, Jose-Luis, Rodriguez, Ana Diaz, Nakano, Tatsumi, Chouza, Fernando, Leblanc, Thierry, Torres, Carlos, Garcia, Omaira, Röhling, Amelie N., Schneider, Matthias, Blumenstock, Thomas, Tully, Matt, Paton-Walsh, Clare, Jones, Nicholas, Querel, Richard, Strahan, Susan, Stauffer, Ryan M., Thompson, Anne M., Inness, Antje, Engelen, Richard, Chang, Kai-Lan, and Cooper, Owen R.
- Abstract
Throughout spring and summer 2020, ozone stations in the northern extratropics recorded unusually low ozone in the free troposphere. From April to August, and from 1 to 8 kilometers altitude, ozone was on average 7% (≈4 nmol/mol) below the 2000 to 2020 climatological mean. Such low ozone, over several months, and at so many stations, has not been observed in any previous year since at least 2000. Atmospheric composition analyses from the Copernicus Atmosphere Monitoring Service and simulations from the NASA GMI model indicate that the large 2020 springtime ozone depletion in the Arctic stratosphere contributed less than one quarter of the observed tropospheric anomaly. The observed anomaly is consistent with recent chemistry-climate model simulations, which assume emissions reductions similar to those caused by the COVID-19 crisis. COVID-19 related emissions reductions appear to be the major cause for the observed reduced free tropospheric ozone in 2020.
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- 2021
38. Mechanism of Ganglioside Receptor Recognition by Botulinum Neurotoxin Serotype E
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Masuyer, Geoffrey, Davies, Jonathan R., Stenmark, Pål, Masuyer, Geoffrey, Davies, Jonathan R., and Stenmark, Pål
- Abstract
The botulinum neurotoxins are potent molecules that are not only responsible for the lethal paralytic disease botulism, but have also been harnessed for therapeutic uses in the treatment of an increasing number of chronic neurological and neuromuscular disorders, in addition to cosmetic applications. The toxins act at the cholinergic nerve terminals thanks to an efficient and specific mechanism of cell recognition which is based on a dual receptor system that involves gangliosides and protein receptors. Binding to surface-anchored gangliosides is the first essential step in this process. Here, we determined the X-ray crystal structure of the binding domain of BoNT/E, a toxin of clinical interest, in complex with its GD1a oligosaccharide receptor. Beyond confirmation of the conserved ganglioside binding site, we identified key interacting residues that are unique to BoNT/E and a significant rearrangement of loop 1228-1237 upon carbohydrate binding. These observations were also supported by thermodynamic measurements of the binding reaction and assessment of ganglioside selectivity by immobilised-receptor binding assays. These results provide a structural basis to understand the specificity of BoNT/E for complex gangliosides.
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- 2021
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39. Crystal structures of NUDT15 variants enabled by a potent inhibitor reveal the structural basis for thiopurine sensitivity
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Rehling, Daniel, Zhang, Si Min, Jemth, Ann-Sofie, Koolmeister, Tobias, Throup, Adam, Wallner, Olov, Scaletti, Emma, Moriyama, Takaya, Nishii, Rina, Davies, Jonathan, Desroses, Matthieu, Rudd, Sean G., Scobie, Martin, Homan, Evert, Warpman Berglund, Ulrika, Yang, Jun J., Helleday, Thomas, Stenmark, Pål, Rehling, Daniel, Zhang, Si Min, Jemth, Ann-Sofie, Koolmeister, Tobias, Throup, Adam, Wallner, Olov, Scaletti, Emma, Moriyama, Takaya, Nishii, Rina, Davies, Jonathan, Desroses, Matthieu, Rudd, Sean G., Scobie, Martin, Homan, Evert, Warpman Berglund, Ulrika, Yang, Jun J., Helleday, Thomas, and Stenmark, Pål
- Abstract
The enzyme NUDT15 efficiently hydrolyzes the active metabolites of thiopurine drugs, which are routinely used for treating cancer and inflammatory diseases. Loss-of-function variants in NUDT15 are strongly associated with thiopurine intolerance, such as leukopenia, and preemptive NUDT15 genotyping has been clinically implemented to personalize thiopurine dosing. However, understanding the molecular consequences of these variants has been difficult, as no structural information was available for NUDT15 proteins encoded by clinically actionable pharmacogenetic variants because of their inherent instability. Recently, the small molecule NUDT15 inhibitor TH1760 has been shown to sensitize cells to thiopurines, through enhanced accumulation of 6-thio-guanine in DNA. Building upon this, we herein report the development of the potent and specific NUDT15 inhibitor, TH7755. TH7755 demonstrates a greatly improved cellular target engagement and 6-thioguanine potentiation compared with TH1760, while showing no cytotoxicity on its own. This potent inhibitor also stabilized NUDT15, enabling analysis by X-ray crystallography. We have determined high-resolution structures of the clinically relevant NUDT15 variants Arg139Cys, Arg139His, Val18Ile, and V18_V19insGlyVal. These structures provide clear insights into the structural basis for the thiopurine intolerance phenotype observed in patients carrying these pharmacogenetic variants. These findings will aid in predicting the effects of new NUDT15 sequence variations yet to be discovered in the clinic.
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- 2021
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40. Evaluating the application of NLP tools in mainstream participatory budgeting processes in Scotland
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Davies, Jonathan, Arana-Catania, Miguel, Procter, Rob, van Lier, Felix-Anselm, He, Yulan, Davies, Jonathan, Arana-Catania, Miguel, Procter, Rob, van Lier, Felix-Anselm, and He, Yulan
- Abstract
In recent years participatory budgeting (PB) in Scotland has grown from a handful of community-led processes to a movement supported by local and national government. This is epitomized by an agreement between the Scottish Government and the Convention of Scottish Local Authorities (COSLA) that at least 1% of local authority budgets will be subject to PB. This ongoing research paper explores the challenges that emerge from this 'scaling up' or 'mainstreaming' across the 32 local authorities that make up Scotland. The main objective is to evaluate local authority use of the digital platform Consul, which applies Natural Language Processing (NLP) to address these challenges. This project adopts a qualitative longitudinal design with interviews, observations of PB processes, and analysis of the digital platform data. Thematic analysis is employed to capture the major issues and themes which emerge. Longitudinal analysis then explores how these evolve over time. The potential for 32 live study sites provides a unique opportunity to explore discrete political and social contexts which materialize and allow for a deeper dive into the challenges and issues that may exist, something a wider cross-sectional study would miss. Initial results show that issues and challenges which come from scaling up may be tackled using NLP technology which, in a previous controlled use case-based evaluation, has shown to improve the effectiveness of citizen participation., Comment: 7 pages, presented at the 14th International Conference on Theory and Practice of Electronic Governance 2021. arXiv admin note: text overlap with arXiv:2109.09517
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- 2021
41. Quantifying the effect of power spectral density uncertainty on gravitational-wave parameter estimation for compact binary sources
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LIGO (Observatory : Massachusetts Institute of Technology), Massachusetts Institute of Technology. Department of Physics, MIT Kavli Institute for Astrophysics and Space Research, Biscoveanu, Sylvia, Haster, Carl-Johan, Vitale, Salvatore, Davies, Jonathan, LIGO (Observatory : Massachusetts Institute of Technology), Massachusetts Institute of Technology. Department of Physics, MIT Kavli Institute for Astrophysics and Space Research, Biscoveanu, Sylvia, Haster, Carl-Johan, Vitale, Salvatore, and Davies, Jonathan
- Abstract
© 2020 American Physical Society. In order to perform Bayesian parameter estimation to infer the source properties of gravitational waves from compact binary coalescences (CBCs), the noise characteristics of the detector must be understood. It is typically assumed that the detector noise is stationary and Gaussian, characterized by a power spectral density (PSD) that is measured with infinite precision. We present a new method to incorporate the uncertainty in the power spectral density estimation into the Bayesian inference of the binary source parameters and apply it to the first 11 CBC detections reported by the LIGO-Virgo Collaboration. We find that incorporating the PSD uncertainty only leads to variations in the positions and widths of the binary parameter posteriors on the order of a few percent.
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- 2021
42. A mixed-methods ethnographic approach to participatory budgeting in Scotland
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Davies, Jonathan, Arana-Catania, M., Procter, Rob, Van Lier, F. A., He, Yulan, Davies, Jonathan, Arana-Catania, M., Procter, Rob, Van Lier, F. A., and He, Yulan
- Abstract
Participatory budgeting (PB) is already well established in Scotland in the form of community led grant-making yet has recently transformed from a grass-roots activity to a mainstream process or embedded 'policy instrument'. An integral part of this turn is the use of the Consul digital platform as the primary means of citizen participation. Using a mixed method approach, this ongoing research paper explores how each of the 32 local authorities that make up Scotland utilise the Consul platform to engage their citizens in the PB process and how they then make sense of citizens' contributions. In particular, we focus on whether natural language processing (NLP) tools can facilitate both citizen engagement, and the processes by which citizens' contributions are analysed and translated into policies., Comment: 6 pages, presented in GoodIT 2021 Conference
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- 2021
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43. From crisis to catastrophe : The death and viral legacies of austere neoliberalism in Europe?
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Standring, Adam, Davies, Jonathan, Standring, Adam, and Davies, Jonathan
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The COVID-19 pandemic is a global event, but what became apparent almost immediately was that while the virus seems indiscriminate, vulnerability and the capacity to mitigate its impact are not spread equally, either between or within countries. Years of austere neoliberalism in Europe have exacerbated inequality and precarity, acting as a 'pre-existing condition' onto which the virus has now landed. The question we ask is: when the pandemic subsides, can the underlying conditions of contemporary neoliberalism remain? And what may replace it?
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- 2020
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44. Structural and Biochemical Characterization of Botulinum Neurotoxin Subtype B2 Binding to Its Receptors
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Davies, Jonathan R., Masuyer, Geoffrey, Stenmark, Pål, Davies, Jonathan R., Masuyer, Geoffrey, and Stenmark, Pål
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Botulinum neurotoxins (BoNTs) can be used therapeutically to treat a wide range of neuromuscular and neurological conditions. A collection of natural BoNT variants exists which can be classified into serologically distinct serotypes (BoNT/B), and further divided into subtypes (BoNT/B1, B2, …). BoNT subtypes share a high degree of sequence identity within the same serotype yet can display large variation in toxicity. One such example is BoNT/B2, which was isolated from Clostridium botulinum strain 111 in a clinical case of botulism, and presents a 10-fold lower toxicity than BoNT/B1. In an effort to understand the molecular mechanisms behind this difference in potency, we here present the crystal structures of BoNT/B2 in complex with the ganglioside receptor GD1a, and with the human synaptotagmin I protein receptor. We show, using receptor-binding assays, that BoNT/B2 has a slightly higher affinity for GD1a than BoNT/B1, and confirm its considerably weaker affinity for its protein receptors. Although the overall receptor-binding mechanism is conserved for both receptors, structural analysis suggests the lower affinity of BoNT/B2 is the result of key substitutions, where hydrophobic interactions important for synaptotagmin-binding are replaced by polar residues. This study provides a template to drive the development of future BoNT therapeutic molecules centered on assessing the natural subtype variations in receptor-binding that appears to be one of the principal stages driving toxicity.
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- 2020
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45. High-resolution crystal structures of the botulinum neurotoxin binding domains from subtypes A5 and A6
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Davies, Jonathan R., Britton, Amy, Liu, Sai Man, Acharya, K. Ravi, Davies, Jonathan R., Britton, Amy, Liu, Sai Man, and Acharya, K. Ravi
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Clostridium botulinumneurotoxins (BoNTs) cause flaccid paralysis through inhibition of acetylcholine release from motor neurons; however, at tiny doses, this property is exploited for use as a therapeutic. Each member of the BoNT family of proteins consists of three distinct domains: a binding domain that targets neuronal cell membranes (H-C), a translocation domain (H-N) and a catalytic domain (LC). Here, we present high-resolution crystal structures of the binding domains of BoNT subtypes/A5 (H-C/A5) and/A6 (H-C/A6). These structures show that the core fold identified in other subtypes is maintained, but with subtle differences at the expected receptor-binding sites.
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- 2020
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46. An EAGLE's View of Ex-situ Galaxy Growth
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Davison, Thomas A., Norris, Mark A., Pfeffer, Joel L., Davies, Jonathan J., Crain, Robert A., Davison, Thomas A., Norris, Mark A., Pfeffer, Joel L., Davies, Jonathan J., and Crain, Robert A.
- Abstract
Modern observational and analytic techniques now enable the direct measurement of star formation histories and the inference of galaxy assembly histories. However, current theoretical predictions of assembly are not ideally suited for direct comparison with such observational data. We therefore extend the work of prior examinations of the contribution of ex-situ stars to the stellar mass budget of simulated galaxies. Our predictions are specifically tailored for direct testing with a new generation of observational techniques by calculating ex-situ fractions as functions of galaxy mass and morphological type, for a range of surface brightnesses. These enable comparison with results from large FoV IFU spectrographs, and increasingly accurate spectral fitting, providing a look-up method for the estimated accreted fraction. We furthermore provide predictions of ex-situ mass fractions as functions of galaxy mass, galactocentric radius and environment. Using $z=0$ snapshots from the 100cMpc$^3$ and 25cMpc$^3$ EAGLE simulations we corroborate the findings of prior studies, finding that ex-situ fraction increases with stellar mass for central and satellite galaxies in a stellar mass range of 2$\times$10$^{7}$ - 1.9$\times$10$^{12}$ M$_{\odot}$. For those galaxies of mass M$_*$>5$\times$10$^{8}$M$_{\odot}$, we find that the total ex-situ mass fraction is greater for more extended galaxies at fixed mass. When categorising satellite galaxies by their parent group/cluster halo mass we find that the ex-situ fraction decreases with increasing parent halo mass at fixed galaxy mass. This apparently counter-intuitive result may be the result of high passing velocities within large cluster halos inhibiting efficient accretion onto individual galaxies., Comment: 16 pages, 11 figures. Accepted for publication in MNRAS
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- 2020
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47. Quenching and morphological evolution due to circumgalactic gas expulsion in a simulated galaxy with a controlled assembly history
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Davies, Jonathan J., Crain, Robert A., Pontzen, Andrew, Davies, Jonathan J., Crain, Robert A., and Pontzen, Andrew
- Abstract
We examine the influence of dark matter halo assembly on the evolution of a simulated $\sim L^\star$ galaxy. Starting from a zoom-in simulation of a star-forming galaxy evolved with the EAGLE galaxy formation model, we use the genetic modification technique to create a pair of complementary assembly histories: one in which the halo assembles later than in the unmodified case, and one in which it assembles earlier. Delayed assembly leads to the galaxy exhibiting a greater present-day star formation rate than its unmodified counterpart, whilst in the accelerated case the galaxy quenches at $z\simeq 1$, and becomes spheroidal. We simulate each assembly history nine times, adopting different seeds for the random number generator used by EAGLE's stochastic subgrid implementations of star formation and feedback. The systematic changes driven by differences in assembly history are significantly stronger than the random scatter induced by this stochasticity. The sensitivity of $\sim L^\star$ galaxy evolution to dark matter halo assembly follows from the close coupling of the growth histories of the central black hole (BH) and the halo, such that earlier assembly fosters the formation of a more massive BH, and more efficient expulsion of circumgalactic gas. In response to this expulsion, the circumgalactic medium reconfigures at a lower density, extending its cooling time and thus inhibiting the replenishment of the interstellar medium. Our results indicate that halo assembly history significantly influences the evolution of $\sim L^\star$ central galaxies, and that the expulsion of circumgalactic gas is a crucial step in quenching them., Comment: 19 pages, 11 figures, accepted for publication in MNRAS. High resolution images and movies are available at https://www.astro.ljmu.ac.uk/~arijdav1/gm_paper.html
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- 2020
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48. High-resolution, 3D radiative transfer modelling III. The DustPedia barred galaxies
- Author
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Nersesian, Angelos, Verstocken, Sam, Viaene, Sebastien, Baes, Maarten, Xilouris, Emmanuel M., Bianchi, Simone, Casasola, Viviana, Clark, Christopher J. R., Davies, Jonathan I., De Looze, Ilse, De Vis, Pieter, Dobbels, Wouter, Fritz, Jacopo, Galametz, Maud, Galliano, Frederic, Jones, Anthony P., Madden, Suzanne C., Mosenkov, Aleksandr V., Trcka, Ana, Ysard, Nathalie, Nersesian, Angelos, Verstocken, Sam, Viaene, Sebastien, Baes, Maarten, Xilouris, Emmanuel M., Bianchi, Simone, Casasola, Viviana, Clark, Christopher J. R., Davies, Jonathan I., De Looze, Ilse, De Vis, Pieter, Dobbels, Wouter, Fritz, Jacopo, Galametz, Maud, Galliano, Frederic, Jones, Anthony P., Madden, Suzanne C., Mosenkov, Aleksandr V., Trcka, Ana, and Ysard, Nathalie
- Abstract
Context: Dust in late-type galaxies in the local Universe is responsible for absorbing approximately one third of the energy emitted by stars. It is often assumed that dust heating is mainly attributable to the absorption of UV and optical photons emitted by the youngest (<= 100 Myr) stars. Consequently, thermal re-emission by dust at FIR wavelengths is often linked to the star-formation activity of a galaxy. However, several studies argue that the contribution to dust heating by much older stars might be more significant. Advances in radiation transfer (RT) simulations finally allow us to actually quantify the heating mechanisms of diffuse dust by the stellar radiation field. Aims: As one of the main goals in the DustPedia project, we have constructed detailed 3D stellar and dust RT models for nearby galaxies. We analyse the contribution of the different stellar populations to the dust heating in four face-on barred galaxies: NGC1365, M83, M95, and M100. We aim to quantify the fraction directly related to young stars, both globally and on local scales, and to assess the influence of the bar on the heating fraction. Results: We derive global attenuation laws for each galaxy and confirm that galaxies of high sSFR have shallower attenuation curves and weaker UV bumps. On average, 36.5% of the bolometric luminosity is absorbed by dust. We report a clear effect of the bar structure on the radial profiles of the dust-heating fraction by the young stars, and the dust temperature. We find that the young stars are the main contributors to the dust heating, donating, on average ~59% of their luminosity to this purpose throughout the galaxy. This dust-heating fraction drops to ~53% in the bar region and ~38% in the bulge region where the old stars are the dominant contributors to the dust heating. We also find a strong link between the heating fraction by the young stars and the sSFR.
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- 2020
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49. High-resolution, 3D radiative transfer modelling. II. The early-type spiral galaxy M81
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Verstocken, Sam, Nersesian, Angelos, Baes, Maarten, Viaene, Sébastien, Bianchi, Simone, Casasola, Viviana, Clark, Christopher J. R., Davies, Jonathan I., De Looze, Ilse, De Vis, Pieter, Dobbels, Wouter, Galliano, FrédÉric, Jones, Anthony P., Madden, Suzanne C., Mosenkov, Aleksandr V., Trčka, Ana, Xilouris, Emmanuel M., Verstocken, Sam, Nersesian, Angelos, Baes, Maarten, Viaene, Sébastien, Bianchi, Simone, Casasola, Viviana, Clark, Christopher J. R., Davies, Jonathan I., De Looze, Ilse, De Vis, Pieter, Dobbels, Wouter, Galliano, FrédÉric, Jones, Anthony P., Madden, Suzanne C., Mosenkov, Aleksandr V., Trčka, Ana, and Xilouris, Emmanuel M.
- Abstract
Interstellar dust absorbs stellar light very efficiently and thus shapes the energetic output of galaxies. Studying the impact of different stellar populations on the dust heating remains hard because it requires decoupling the relative geometry of stars and dust, and involves complex processes as scattering and non-local dust heating. We aim to constrain the relative distribution of dust and stellar populations in the spiral galaxy M81 and create a realistic model of the radiation field that describes the observations. Investigating the dust-starlight interaction on local scales, we want to quantify the contribution of young and old stellar populations to the dust heating. We aim to standardise the setup and model selection of such inverse radiative transfer simulations so this can be used for comparable modelling of other nearby galaxies. We present a semi-automated radiative transfer modelling pipeline that implements the necessary steps such as the geometric model construction and the normalisation of the components through an optimisation routine. We use the Monte Carlo radiative transfer code SKIRT to calculate a self-consistent, panchromatic model of the interstellar radiation field. By looking at different stellar populations independently, we can quantify to what extent different stellar age populations contribute to the dust heating. Our method takes into account the effects of non-local heating. We obtain a realistic 3D radiative transfer model of the face-on galaxy M81. We find that only 50.2\% of the dust heating can be attributed to young stellar populations. We confirm a tight correlation between the specific star formation rate and the heating fraction by young stellar populations, both in sky projection and in 3D, also found for radiative transfer models of M31 and M51. We conclude that... (abridged), Comment: 23 pages, 16 figures, accepted for publication in A&A
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- 2020
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50. Quantifying the Effect of Power Spectral Density Uncertainty on Gravitational-Wave Parameter Estimation for Compact Binary Sources
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Biscoveanu, Sylvia, Haster, Carl-Johan, Vitale, Salvatore, Davies, Jonathan, Biscoveanu, Sylvia, Haster, Carl-Johan, Vitale, Salvatore, and Davies, Jonathan
- Abstract
In order to perform Bayesian parameter estimation to infer the source properties of gravitational waves from compact binary coalescences (CBCs), the noise characteristics of the detector must be understood. It is typically assumed that the detector noise is stationary and Gaussian, characterized by a power spectral density (PSD) that is measured with infinite precision. We present a new method to incorporate the uncertainty in the power spectral density estimation into the Bayesian inference of the binary source parameters and apply it to the first 11 CBC detections reported by the LIGO- Virgo Collaboration. We find that incorporating the PSD uncertainty only leads to variations in the positions and widths of the binary parameter posteriors on the order of a few percent. Our results are publicly available for download on git [1].
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- 2020
- Full Text
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