Gatekeeping processes: grounded theory, young people and physical activity

This thesis has two purposes: firstly, to develop grounded theory methodology and secondly, to apply it in order to establish and further investigate those processes which structure young peoples' participation in physical activity. To satisfy the first of these aims, the Helix Model was created to provide a systematic framework to the grounded theory analysis. This Model was then employed to address the second aim, as it was used to analyse interviews conducted with a mixed sex sample of twenty nine very active and very inactive children and their parents. These young people were selected as a result of completing, on four occasions, a 24 hour self-report questionnaire specifically designed for them. The grounded theory analysis identified a series of interrelated 'gatekeeping processes' which construct those opportunities for young people to participate in physical activity. Several evolving processes, varying according to the context and nature of the physical activity, interrelate with one another to create a complex causal web. The gatekeeping processes are consciously, as well as unconsciously, manipulated relative to the social and physical context in which the young person and the other gatekeeping agents (parents, school, peers) exist and find themselves. The interrelationships between these agents, especially the young person and their parents, work through compromise and coercion to satisfy each of their personal agendas. The nature of each agenda is based on the definition associated with the three roles which gatekeepers adopt (guardian, facilitator, enforcer). The definition of each role affects the manner in which young people individually, as well as collectively with the gatekeepers, construct networks to accomplish an evolving combination of: independence, maximisation of the available resources, rewards, and care and control. The interrelationship between these factors and the extent to which participation in physical activity can achieve them, is what determines the likelihood of the young person's participation in that activity. However, physical activity has to compete with a myriad of the other activities the young person is involved in. These are activities, which for the more sedentary young person, are perceived to be more successful at providing the desired rewards

Conformation of the Deoxyribonucleic Acid-Binding Peptide Antibiotic Echinomycin Based on Energy Calculations

SUMMARY UGHETTO, GIOVANN

An intervention to facilitate 'high quality' physical education - from gymnastics to athletics

The summer edition of Research Matters included a short article on facilitating ‘high quality’ physical education and ‘high quality’ gymnastics in a city school (see Cale et al., 2011). The article provided a summary of the first phase of a research project which aimed to: i) facilitate high quality teaching and learning in physical education, and ii) identify key principles that contribute to high quality outcomes and which could be applied across the physical education curriculum. This article follows on and presents a summary of phase 2 of the research, which focused on athletics, as well as of the key findings and recommendations from the project overall

Renewing the Exploration Approach for Mid-Enthalpy Systems: Examples from Northern England and Scotland

After a promising start in the 1970s and 80s, the UK rather fell behind other countries in the search for viable mid-enthalpy geothermal resources. This situation began to turn around in 2004, when the first of three deep geothermal exploration boreholes were drilled in northern England. What distinguished these from earlier drilling in Cornwall was the deliberate search for naturallyhigh permeability associated with major faults, especially those that have undergone strike-slip reactivation during the Cenozoic. Boreholes at Eastgate in the North Pennines targeted buried radiothermal granite, whereas the 1,821m-deep Science Central Borehole in Newcastle upon Tyne targeted a postulated deep sedimentary aquifer (the Fell Sandstones), which were inferred to be connected laterally to the granitic heat source by a major fault (the reactivation of the Iapetus geo-suture). The drilling was in both cases rewarded with impressive heat flows, and in the case of Eastgate with what is believed to be the highest permeability yet found in a deep granite batholith anywhere in the world. In parallel with these developments, a re-assessment was made of the preexisting geothermal heat flow database for the UK, applying newly-standardised correction protocols for palaeoclimatic and topographic distortions, which were found to be particularly marked in Scotland (where only shallow boreholes had been used to establish geothermal gradients in the original 1980s analysis), Similar prospects in northern England (similar to that drilled at Science Central) are now the focus of commercial exploration efforts. Appraisal of fault dispositions relative to the present-day maximum compressive stress azimuth are being used to identify the most promising areas for intersecting fault-related permeability at depth. New geophysical tools – most notably atomic dielectric resonance scanning – are also being appraised for their ability to directly detect features (such as hot brines) which are indicative of localised convection in target fault zones and aquifers

Inhibition of DNA polymerase reactions by pyrimidine nucleotide analogues lacking the 2-keto group

To investigate the influence of the pyrimidine 2-keto group on selection of nucleotides for incorporation into DNA by polymerases, we have prepared two C nucleoside triphosphates that are analogues of dCTP and dTTP, namely 2-amino-5-(2′-deoxy-β-d-ribofuranosyl) pyridine-5′-triphosphate (d*CTP) and 5-(2′-deoxy-β-d-ribofuranosyl)-3-methyl-2-pyridone-5′-triphosphate (d*TTP) respectively. Both proved strongly inhibitory to PCR catalysed by Taq polymerase; d*TTP rather more so than d*CTP. In primer extension experiments conducted with either Taq polymerase or the Klenow fragment of Escherichia coli DNA polymerase I, both nucleotides failed to substitute for their natural pyrimidine counterparts. Neither derivative was incorporated as a chain terminator. Their capacity to inhibit DNA polymerase activity may well result from incompatibility with the correctly folded form of the polymerase enzyme needed to stabilize the transition state and catalyse phosphodiester bond formatio

Structural correlates of antimicrobial efficacy in IL-8 and related human kinocidins

AbstractChemokines are small (8–12 kDa) effector proteins that potentiate leukocyte chemonavigation. Beyond this role, certain chemokines have direct antimicrobial activity against human pathogenic organisms; such molecules are termed kinocidins. The current investigation was designed to explore the structure–activity basis for direct microbicidal activity of kinocidins. Amino acid sequence and 3-dimensional analyses demonstrated these molecules to contain iterations of the conserved γ-core motif found in broad classes of classical antimicrobial peptides. Representative CXC, CC and C cysteine-motif-group kinocidins were tested for antimicrobial activity versus human pathogenic bacteria and fungi. Results demonstrate that these molecules exert direct antimicrobial activity in vitro, including antibacterial activity of native IL-8 and MCP-1, and microbicidal activity of native IL-8. To define molecular determinants governing its antimicrobial activities, the IL-8 γ-core (IL-8γ) and α-helical (IL-8α) motifs were compared to native IL-8 for antimicrobial efficacy in vitro. Microbicidal activity recapitulating that of native IL-8 localized to the autonomous IL-8α motif in vitro, and demonstrated durable microbicidal activity in human blood and blood matrices ex vivo. These results offer new insights into the modular architecture, context-related deployment and function, and evolution of host defense molecules containing γ-core motifs and microbicidal helices associated with antimicrobial activity

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.

With a resurgence in interest in covalent drugs, there is a need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as a cysteine reactive warhead is employed to target Cys788 in c-KIT, where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification while avoiding some of the limitations generally associated with established moieties

Site-Specific Mutation of the Sensor Kinase GraS in Staphylococcus aureus Alters the Adaptive Response to Distinct Cationic Antimicrobial Peptides

The Staphylococcus aureus two-component regulatory system, GraRS, is involved in resistance to killing by distinct host defense cationic antimicrobial peptides (HD-CAPs). It is believed to regulate downstream target genes such as mprF and dltABCD to modify the S. aureus surface charge. However, the detailed mechanism(s) by which the histidine kinase, GraS, senses specific HD-CAPs is not well defined. Here, we studied a well-characterized clinical methicillin-resistant S. aureus (MRSA) strain (MW2), its isogenic graS deletion mutant (ΔgraS strain), a nonameric extracellular loop mutant (ΔEL strain), and four residue-specific ΔEL mutants (D37A, P39A, P39S, and D35G D37G D41G strains). The ΔgraS and ΔEL strains were unable to induce mprF and dltA expression and, in turn, demonstrated significantly increased susceptibilities to daptomycin, polymyxin B, and two prototypical HD-CAPs (hNP-1 and RP-1). Further, P39A, P39S, and D35G-D37G-D41G ΔEL mutations correlated with moderate increases in HD-CAP susceptibility. Reductions of mprF and dltA induction by PMB were also found in the ΔEL mutants, suggesting these residues are pivotal to appropriate activation of the GraS sensor kinase. Importantly, a synthetic exogenous soluble EL mimic of GraS protected the parental MW2 strain against hNP-1- and RP-1-mediated killing, suggesting a direct interaction of the EL with HD-CAPs in GraS activation. In vivo, the ΔgraS and ΔEL strains displayed dramatic reductions in achieved target tissue MRSA counts in an endocarditis model. Taken together, our results provide new insights into potential roles of GraS in S. aureus sensing of HD-CAPs to induce adaptive survival responses to these molecules

Gait Speed and Mood, Cognition, and Quality of Life in Older Adults With Atrial Fibrillation

Background: Low gait speed has been linked with impaired mood, cognition, and quality of life (QOL) in older adults. We examined whether low gait speed was associated with impaired mood, cognition, and QOL among older adults with atrial fibrillation (AF). Methods and Results: Participants (n=1185) had a diagnosis of AF, aged \u3e /=65 years, CHA2DS2VASc \u3e /=2 and had no contraindications to anticoagulation. Participants completed a 15-foot walk test, and low gait speed was categorized using cutoffs from the Fried Frailty Index. Participants self-reported measures of depressive symptoms (Patient Health Questionnaire 9 \u3e /=10), anxiety symptoms (Generalized Anxiety Disorder 7 \u3e /=10), cognitive impairment (Montreal Cognitive Assessment \u3c /=23), and potentially impaired Atrial Fibrillation Effect Quality-of-Life Questionnaire \u3c 80. Participants were on average aged 75.3 (SD: 7.0) years, 48.0% were women, and 85.5% were non-Hispanic white; 85.6% were taking an oral anticoagulant, 26.1% had low gait speed, 8.4% had elevated depressive symptoms, 5.7% had elevated anxiety symptoms, 41.1% were cognitively impaired, and 41.6% had potentially impaired AF-related QOL. Participants with low gait speed were significantly more likely to have elevated depressive symptoms (adjusted odds ratio: 2.1, 95% CI: 1.3-3.4), elevated anxiety symptoms (adjusted odds ratio: 2.2, 95% CI: 1.2-3.9), and cognitive impairment (adjusted odds ratio: 1.5, 95% CI: 1.1-2.1). Impaired AF-related QOL did not differ by gait speed after adjustment for clinical characteristics (adjusted odds ratio: 1.1, 95% CI: 0.8-1.5). Conclusions: Twenty-six percent of older adults with AF had low gait speed, and low gait speed was associated with impaired mood and cognition. Further research is needed to determine whether declines in gait speed lead to impaired mood and cognition or whether these conditions develop concurrently