Applying forces to elastic network models of large biomolecules using a haptic feedback device

Elastic network models of biomolecules have proved to be relatively good at predicting global conformational changes particularly in large systems. Software that facilitates rapid and intuitive exploration of conformational change in elastic network models of large biomolecules in response to externally applied forces would therefore be of considerable use, particularly if the forces mimic those that arise in the interaction with a functional ligand. We have developed software that enables a user to apply forces to individual atoms of an elastic network model of a biomolecule through a haptic feedback device or a mouse. With a haptic feedback device the user feels the response to the applied force whilst seeing the biomolecule deform on the screen. Prior to the interactive session normal mode analysis is performed, or pre-calculated normal mode eigenvalues and eigenvectors are loaded. For large molecules this allows the memory and number of calculations to be reduced by employing the idea of the important subspace, a relatively small space of the first M lowest frequency normal mode eigenvectors within which a large proportion of the total fluctuation occurs. Using this approach it was possible to study GroEL on a standard PC as even though only 2.3% of the total number of eigenvectors could be used, they accounted for 50% of the total fluctuation. User testing has shown that the haptic version allows for much more rapid and intuitive exploration of the molecule than the mouse version

Interacting with the biomolecular solvent accessible surface via a haptic feedback device

Background: From the 1950s computer based renderings of molecules have been produced to aid researchers in their understanding of biomolecular structure and function. A major consideration for any molecular graphics software is the ability to visualise the three dimensional structure of the molecule. Traditionally, this was accomplished via stereoscopic pairs of images and later realised with three dimensional display technologies. Using a haptic feedback device in combination with molecular graphics has the potential to enhance three dimensional visualisation. Although haptic feedback devices have been used to feel the interaction forces during molecular docking they have not been used explicitly as an aid to visualisation. Results: A haptic rendering application for biomolecular visualisation has been developed that allows the user to gain three-dimensional awareness of the shape of a biomolecule. By using a water molecule as the probe, modelled as an oxygen atom having hard-sphere interactions with the biomolecule, the process of exploration has the further benefit of being able to determine regions on the molecular surface that are accessible to the solvent. This gives insight into how awkward it is for a water molecule to gain access to or escape from channels and cavities, indicating possible entropic bottlenecks. In the case of liver alcohol dehydrogenase bound to the inhibitor SAD, it was found that there is a channel just wide enough for a single water molecule to pass through. Placing the probe coincident with crystallographic water molecules suggests that they are sometimes located within small pockets that provide a sterically stable environment irrespective of hydrogen bonding considerations. Conclusion: By using the software, named HaptiMol ISAS (available from http://​www.​haptimol.​co.​uk), one can explore the accessible surface of biomolecules using a three-dimensional input device to gain insights into the shape and water accessibility of the biomolecular surface that cannot be so easily attained using conventional molecular graphics software

A Simple Non-equilibrium Feedback Model for Galaxy-Scale Star Formation: Delayed Feedback and SFR Scatter

We explore a class of simple non-equilibrium star formation models within the framework of a feedback-regulated model of the ISM, applicable to kiloparsec-scale resolved star formation relations (e.g. Kennicutt-Schmidt). Combining a Toomre-Q-dependent local star formation efficiency per free-fall time with a model for delayed feedback, we are able to match the normalization and scatter of resolved star formation scaling relations. In particular, this simple model suggests that large ($\sim$dex) variations in star formation rates (SFRs) on kiloparsec scales may be due to the fact that supernova feedback is not instantaneous following star formation. The scatter in SFRs at constant gas surface density in a galaxy then depends on the properties of feedback and when we observe its star-forming regions at various points throughout their collapse/star formation "cycles". This has the following important observational consequences: (1) the scatter and normalization of the Kennicutt-Schmidt relation are relatively insensitive to the local (small-scale) star formation efficiency, (2) but gas depletion times and velocity dispersions are; (3) the scatter in and normalization of the Kennicutt-Schmidt relation is a sensitive probe of the feedback timescale and strength; (4) even in a model where $\tilde Q_{\rm gas}$ deterministically dictates star formation locally, time evolution, variation in local conditions (e.g., gas fractions and dynamical times), and variations between galaxies can destroy much of the observable correlation between SFR and $\tilde Q_{\rm gas}$ in resolved galaxy surveys. Additionally, this model exhibits large scatter in SFRs at low gas surface densities, in agreement with observations of flat outer HI disk velocity dispersion profiles.Comment: 15 pages, 6 figures, accepted by MNRAS (04/25/2019

Advertising and Dublin’s Consumer Culture in James Joyce’s Ulysses

This thesis reconsiders James Joyce’s representation of advertising and Dublin’s consumer culture in Ulysses. Against earlier, generalising accounts, it applies a carefully historicising methodology to demonstrate the cultural specificity of Joyce’s engagement. It does so in three ways. To begin with, it establishes that Irish consumerism did not simply follow British advances, but developed in a distinct and inflected fashion. Chapters 2 and 3 show that while Joyce incorporates all of the material characteristics of Dublin’s relatively advanced consumer culture, he downplays its advertising industry, making it appear less developed in 1904 than was historically the case. Secondly, it analyses the distortions introduced by Joyce’s own historical remove from the consumer culture he depicts. Chapter 4 identifies for the first time the sources of Joyce’s “Advertising” notes from his so-called “Notes on Business and Commerce,” and establishes that his representation of Bloom’s advertising consciousness reflects advances in advertising theory that only got seriously underway in the decade between 1904, when the novel is set, and 1914, when Joyce began to write it. Finally, having analysed the material and compositional background to Joyce’s portrayal of early-twentieth-century consumerism, this thesis analyses Joyce’s engagement with two of its dominant ideologies. Chapter 5 concentrates on the ‘Lestrygonians’ and ‘Ithaca’ episodes to argue that Joyce lays bare the overdetermined nature of colonial consumption, depicting the naturalisation of British commodities on the Irish market, and contesting the spurious claim to disinterestedness presented by imperial consumerist discourses. Chapter 6 develops intertextual readings of the ‘Nausicaa’ chapter to show that Joyce’s narrative is even more fully comprised of the language of female-oriented advertising than has been recognised. It argues that the chapter responds to a particular ideological complex, in which consumerist imperatives struggled with more conservative patriarchal interests. Overall, this thesis brings together historical, genetic and intertextual critical approaches to uncover the stylistic and chronological manipulations involved in Joyce’s fictionalisation of early-twentieth-century Irish consumerism. It argues that Ulysses stands as both a reflection of this crucial period of socio-economic change, and a politicised response to its dominant ideological coercions

Elucidating the factors that define host species ranges of Salmonella enterica serovars

Salmonella enterica is an important zoonotic pathogen of clinical and veterinary significance. The species is divided into seven subspecies; subspecies I, enterica, is further divided in to Over 1530 serovars based on different epitopes of two surface antigens. Clinical and veterinary isolalions of Salmonella are frequently typed to the serovar level of classirication. This epidemiological data shows that some serovars are isolated from distinct subsets of species. In this study I have focused on two serovars, S. Derby and S. Mbandaka, which are frequently isolated from distinct subsets of livestock species in the UK. The majority of S. Derby isolations are from pigs and turkeys, whereas the majority of S. Mbandaka isolations are from cattle and chickens. To begin to identify potential mechanisms of host adaptation, I sequenced two strains of each serovar and compared their nucleotide sequences and functional annotations. This lead to the discovery of a new Salmonella pathogenicity is land, SPI-23, in the chromosome sequence of S. Derby, that I go on to show is regulated in a ti ssue specific manner in a porcine Ivac model. Mutagenesis of the most highly upregulated gene with in SPI-23 , po/R, generated unique phenotypes that have enabled me to pos it a ro le for SPI-23 in tropism to porcine jejunum. To interrogate the role of metabolite utilisation in constraining co loni sation of certain niches, I performed high-th roughput phenotyping using Biolog phenotypic microarray technology, at ambient and body temperature!;, under aerobic and anaerobic conditions. This, along with other phenotypic studies, lead me to propose a partitioned niche model 3 Matthew R. Hayward: Thesis between host adaptation in the case of S. Derby and adaptation to persistencc in the environment on soybean based feed in the case of S. Mbandaka. To identify the contribution of an environmcnt composed of a complex set of mctabolites 10 host adaptation, I produced genome-scale metabol ic reconstructions for both serovars. The models were confronted with metabolites found in porcine colon and jejunum; these I identified through metabolomics of gut sections using NMR. These models were used to observe which transport and secondary metabolic reactions contribute most to the incorporation of biomass by S. Derby and S. Mbandaka when in a porcine host. Finally I relate the lindings of these studies to a representat ive population of isolates, for which' have produced a phylogenetic recon struction. I discovered two di stinct lineages of S. Derby each with a distinct set of genotypes and phenotypes. I postulate that one lineage is adapted La turkeys and environmental persistence, and the other adapted to pathogenicity in figs. 1 also show that S. Mbandaka is clonal in thc UK, and is adapted to growth in soybean based feeds. at ambient temperatures and is adapted to environmental persistence. 4EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Corticosteroids for the common cold

BACKGROUND: The common cold is a frequent illness, which, although benign and self limiting, results in many consultations to primary care and considerable loss of school or work days. Current symptomatic treatments have limited benefit. Corticosteroids are an effective treatment in other upper respiratory tract infections and their anti‐inflammatory effects may also be beneficial in the common cold. This updated review has included one additional study. OBJECTIVES: To compare corticosteroids versus usual care for the common cold on measures of symptom resolution and improvement in children and adults. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 4), which includes the Acute Respiratory Infections (ARI) Group's Specialised Register, the Database of Reviews of Effects (DARE) (2015, Issue 2), NHS Health Economics Database (2015, Issue 2), MEDLINE (1948 to May week 3, 2015) and EMBASE (January 2010 to May 2015). SELECTION CRITERIA: Randomised, double‐blind, controlled trials comparing corticosteroids to placebo or to standard clinical management. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We were unable to perform meta‐analysis and instead present a narrative description of the available evidence. MAIN RESULTS: We included three trials (353 participants). Two trials compared intranasal corticosteroids to placebo and one trial compared intranasal corticosteroids to usual care; no trials studied oral corticosteroids. In the two placebo‐controlled trials, no benefit of intranasal corticosteroids was demonstrated for duration or severity of symptoms. The risk of bias overall was low or unclear in these two trials. In a trial of 54 participants, the mean number of symptomatic days was 10.3 in the placebo group, compared to 10.7 in those using intranasal corticosteroids (P value = 0.72). A second trial of 199 participants reported no significant differences in the duration of symptoms. The single‐blind trial in children aged two to 14 years, who were also receiving oral antibiotics, had inadequate reporting of outcome measures regarding symptom resolution. The overall risk of bias was high for this trial. Mean symptom severity scores were significantly lower in the group receiving intranasal steroids in addition to oral amoxicillin. One placebo‐controlled trial reported the presence of rhinovirus in nasal aspirates and found no differences. Only one of the three trials reported on adverse events; no differences were found. Two trials reported secondary bacterial infections (one case of sinusitis, one case of acute otitis media; both in the corticosteroid groups). A lack of comparable outcome measures meant that we were unable to combine the data. AUTHORS' CONCLUSIONS: Current evidence does not support the use of intranasal corticosteroids for symptomatic relief from the common cold. However, there were only three trials, one of which was very poor quality, and there was limited statistical power overall. Further large, randomised, double‐blind, placebo‐controlled trials in adults and children are required to answer this question