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Search Results: 1 - 10 of 487307 matches for " John A Parkinson "
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Insights into DNA Platination within Unusual Structural Settings
Stephanie Harvie,Owen Wilson,John A. Parkinson
International Journal of Inorganic Chemistry , 2011, DOI: 10.1155/2011/319757
Abstract: 2D HSQC NMR spectroscopy has been used to monitor reaction and product formation between and nucleic acids possessing irregular topologies and containing site-specific phosphorothioate substitution in the phosphodiester backbone. Comparison of the reaction profiles of dimer nucleic acids with and without phosphorothioate substitution is made with their short nucleic acid counterparts containing the key dimer components. Whereas d(GpA) is relatively unreactive towards , NMR evidence suggests that the tandem sheared mismatch duplex d(GCG3pAGC)2 reacts to form the head-to-tail interstrand G3-N7-Pt-G3-N7 cross-link. The equivalent phosphorothioate R,S-d(GsA) reacts to form a monoiodo, monosulphur adduct, whereas the tandem sheared mismatch phosphorothioate duplex d(GCGsAG5C)2 (VIs) reacts to form the unusual intrastrand macrochelate , in which platinum is attached at both sulphur and G5-N7. Experimental evidence supports the formation of a stabilized mismatch duplex in which platinum is attached to two nitrogen centres in the sequence d(CGCGpTGCG) in contrast to R,S-d(CGCGsT5GCG) for which NMR evidence supports macrochelate-stabilized hairpin loop formation cross-linked at both phosphorothioate sulphur and T5-N3. 1. Introduction The concept of targeted approaches to cancer chemotherapy is increasingly delivering candidate innovations with real potential for application in the clinic [1–3]. Distress to patients caused through the toxic side-effects brought about by systemic delivery of active drugs could be reduced or perhaps eliminated in instances where a cancer is localized, and an inactive prodrug could be delivered and activated solely at the target site, either through reduction within the cell [4] or by means of some external stimulation mechanism [5, 6]. The aim of such localization together with the specific targeting of genes associated with cell immortalization is of real value in the development of new candidate targeting drugs. The branch of anticancer drug therapy involving metallodrugs, especially those based on the platinum compound cisplatin (cis-diamminedichloroplatinum (II)) has seen particular success in the treatment of testicular, bladder, lung, stomach, and ovarian cancers [7] combined with the development of a wide number of analogues developed in attempts to overcome drug resistance [8]. The concept of directing platinum to a specific site involving sulphur was previously explored by examining the reactivity of phosphorothioate-containing monomer nucleotides in order to investigate their potential use in aiding cross-link formation
Mapping the Dark Energy with Varying Alpha
David Parkinson,Bruce A. Bassett,John D. Barrow
Physics , 2003, DOI: 10.1016/j.physletb.2003.10.081
Abstract: Cosmological dark energy is a natural source of variation of the fine structure constant. Using a model-independent approach we show that once general assumptions about the alpha-varying interactions are made, astronomical probes of its variation constrain the dark energy equation of state today to satisfy -1 < w_f < -0.96 at 3-sigma and significantly disfavour late-time changes in the equation of state. We show how dark-energy-induced spatial perturbations of alpha are linked to violations of the Equivalence Principle and are thus negligible at low-redshift, in stark contrast to the BSBM theories. This provides a new test of dark energy as the source of alpha variation.
Neural Correlates of Appetite and Hunger-Related Evaluative Judgments
Richard M. Piech, Jade Lewis, Caroline H. Parkinson, Adrian M. Owen, Angela C. Roberts, Paul E. Downing, John A. Parkinson
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006581
Abstract: How much we desire a meal depends on both the constituent foods and how hungry we are, though not every meal becomes more desirable with increasing hunger. The brain therefore needs to be able to integrate hunger and meal properties to compute the correct incentive value of a meal. The present study investigated the functional role of the amygdala and the orbitofrontal cortex in mediating hunger and dish attractiveness. Furthermore, it explored neural responses to dish descriptions particularly susceptible to value-increase following fasting. We instructed participants to rate how much they wanted food menu items while they were either hungry or sated, and compared the rating differences in these states. Our results point to the representation of food value in the amygdala, and to an integration of attractiveness with hunger level in the orbitofrontal cortex. Dishes particularly desirable during hunger activated the thalamus and the insula. Our results specify the functions of evaluative structures in the context of food attractiveness, and point to a complex neural representation of dish qualities which contribute to state-dependent value.
Optimizing microsurgical skills with EEG neurofeedback
Tomas Ros, Merrick J Moseley, Philip A Bloom, Larry Benjamin, Lesley A Parkinson, John H Gruzelier
BMC Neuroscience , 2009, DOI: 10.1186/1471-2202-10-87
Abstract: National Health Service trainee ophthalmic microsurgeons (N = 20) were randomly assigned to either Sensory Motor Rhythm-Theta (SMR) or Alpha-Theta (AT) groups, a randomized subset of which were also part of a wait-list 'no-treatment' control group (N = 8). Neurofeedback groups received eight 30-minute sessions of EEG training. Pre-post assessment included a skills lab surgical procedure with timed measures and expert ratings from video-recordings by consultant surgeons, together with state/trait anxiety self-reports. SMR training demonstrated advantages absent in the control group, with improvements in surgical skill according to 1) the expert ratings: overall technique (d = 0.6, p < 0.03) and suture task (d = 0.9, p < 0.02) (judges' intraclass correlation coefficient = 0.85); and 2) with overall time on task (d = 0.5, p = 0.02), while everyday anxiety (trait) decreased (d = 0.5, p < 0.02). Importantly the decrease in surgical task time was strongly associated with SMR EEG training changes (p < 0.01), especially with continued reduction of theta (4–7 Hz) power. AT training produced marginal improvements in technique and overall performance time, which were accompanied by a standard error indicative of large individual differences. Notwithstanding, successful within session elevation of the theta-alpha ratio correlated positively with improvements in overall technique (r = 0.64, p = 0.047).SMR-Theta neurofeedback training provided significant improvement in surgical technique whilst considerably reducing time on task by 26%. There was also evidence that AT training marginally reduced total surgery time, despite suboptimal training efficacies. Overall, the data set provides encouraging evidence of optimised learning of a complex medical specialty via neurofeedback training.The use of EEG biofeedback technology (neurofeedback) to self-regulate brainwave frequencies with the aim of recovering or optimising function and performance is becoming increasingly established. I
Modelling the Self-Assembly of Elastomeric Proteins Provides Insights into the Evolution of Their Domain Architectures
Hongyan Song,John Parkinson
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002406
Abstract: Elastomeric proteins have evolved independently multiple times through evolution. Produced as monomers, they self-assemble into polymeric structures that impart properties of stretch and recoil. They are composed of an alternating domain architecture of elastomeric domains interspersed with cross-linking elements. While the former provide the elasticity as well as help drive the assembly process, the latter serve to stabilise the polymer. Changes in the number and arrangement of the elastomeric and cross-linking regions have been shown to significantly impact their assembly and mechanical properties. However, to date, such studies are relatively limited. Here we present a theoretical study that examines the impact of domain architecture on polymer assembly and integrity. At the core of this study is a novel simulation environment that uses a model of diffusion limited aggregation to simulate the self-assembly of rod-like particles with alternating domain architectures. Applying the model to different domain architectures, we generate a variety of aggregates which are subsequently analysed by graph-theoretic metrics to predict their structural integrity. Our results show that the relative length and number of elastomeric and cross-linking domains can significantly impact the morphology and structural integrity of the resultant polymeric structure. For example, the most highly connected polymers were those constructed from asymmetric rods consisting of relatively large cross-linking elements interspersed with smaller elastomeric domains. In addition to providing insights into the evolution of elastomeric proteins, simulations such as those presented here may prove valuable for the tuneable design of new molecules that may be exploited as useful biomaterials.
Impaired gluconeogenesis in a porcine model of paracetamol induced acute liver failure
Konstantinos J Dabos, Henry R Whalen, Philip N Newsome, John A Parkinson, Neil C Henderson, Ian H Sadler, Peter C Hayes, John N Plevris
World Journal of Gastroenterology , 2011,
Abstract: AIM: To investigate glucose homeostasis and in particular gluconeogenesis in a large animal model of acute liver failure (ALF).METHODS: Six pigs with paracetamol induced ALF under general anaesthesia were studied over 25 h. Plasma samples were withdrawn every five hours from a central vein. Three animals were used as controls and were maintained under anaesthesia only. Using 1H NMR spectroscopy we identified most gluconeogenic amino acids along with lactate and pyruvate in the animal plasma samples.RESULTS: No significant changes were observed in the concentrations of the amino acids studied in the animals maintained under anaesthesia only. If we look at the ALF animals, we observed a statistically significant rise of lactate (P < 0.003) and pyruvate (P < 0.018) at the end of the experiments. We also observed statistically significant rises in the concentrations of alanine (P < 0.002), glycine (P < 0.005), threonine (P < 0.048), tyrosine (P < 0.000), phenylalanine (P < 0.000) and isoleucine (P < 0.01). Valine levels decreased significantly (P < 0.05).CONCLUSION: Our pig model of ALF is characterized by an altered gluconeogenetic capacity, an impaired tricarboxylic acid (TCA) cycle and a glycolytic state.
Caenorhabditis elegans—Applications to Nematode Genomics
William F. Gregory,John Parkinson
Comparative and Functional Genomics , 2003, DOI: 10.1002/cfg.260
Abstract: The complete genome sequence of the free-living nematode Caenorhabditis elegans was published 4 years ago. Since then, we have seen great strides in technologies that seek to exploit this data. Here we describe the application of some of these techniques and other advances that are helping us to understand about not only the biology of this important model organism but also the entire phylum Nematoda.
The global landscape of sequence diversity
José Peregrín-álvarez, John Parkinson
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-11-r238
Abstract: Comparisons with prokaryotic datasets reveal a greater genetic diversity within eukaryotes that may be related to differences in modes of genetic inheritance. Mapping this diversity within a phylogenetic framework revealed that the majority of sequences are either highly conserved or specific to the species or taxon from which they derive. Between these two extremes, several evolutionary landmarks consisting of large numbers of sequences conserved within specific taxonomic groups were identified. For example, 8% of sequences derived from metazoan species are specific and conserved within the metazoan lineage. Many of these sequences likely mediate metazoan specific functions, such as cell-cell communication and differentiation.Through the use of partial genome datasets, this study provides a unique perspective of sequence conservation across the three domains of life. The provision of taxon restricted sequences should prove valuable for future computational and biochemical analyses aimed at understanding evolutionary and functional relationships.Sequence space - the sum of all distinct protein and DNA sequences - is vast. A single copy of every possible 300 residue protein, for example, would fill several universes [1]. In consequence, the evolution of genes, which mainly occurs through duplication, divergence and recombination [2], has led to only a small sampling of the available space. Systematic comparisons of proteins and coding sequences from existing genome scale datasets from a wide variety of organisms [3] are beginning to yield insights into the generation and extent of sequence diversity across life [4-9]. In addition to the continued discovery of apparently novel genes and gene families with each new sampled organism, these studies are beginning to reveal a wide spectrum of sequence specificity. At one extreme, sequences may be highly conserved across many different species from several evolutionarily distant lineages. The identification of these conserv
Making sense of EST sequences by CLOBBing them
John Parkinson, David B Guiliano, Mark Blaxter
BMC Bioinformatics , 2002, DOI: 10.1186/1471-2105-3-31
Abstract: As part of our ongoing EST programs investigating 'orphan' genomes, we have developed a clustering algorithm, CLOBB (Cluster on the basis of BLAST similarity) to identify and cluster ESTs. CLOBB may be used incrementally, preserving original cluster designations. It tracks cluster-specific events such as merging, identifies 'superclusters' of related clusters and avoids the expansion of chimeric clusters. Based on the Perl scripting language, CLOBB is highly portable relying only on a local installation of NCBI's freely available BLAST executable and can be usefully applied to > 95 % of the current EST datasets. Analysis of the Danio rerio EST dataset demonstrates that CLOBB compares favourably with two less portable systems, UniGene and TIGR Gene Indices.CLOBB provides a highly portable EST clustering solution and is freely downloaded from: http://www.nematodes.org/CLOBB webciteExpressed sequence tags (EST) are single pass sequence reads from randomly selected cDNA clones that sample the diversity of genes expressed by an organism [1]. ESTs are a valuable adjunct to whole genome sequencing, as they facilitate gene identification. For organisms where whole genome sequencing is a distant goal, EST analysis is a highly cost-effective gene discovery method. The utility of ESTs is illustrated by the phylogenetic diversity of organisms represented in dbEST, the NCBI's EST database [2].Random sampling of clones means that redundancy can be expected in EST datasets, even those derived from normalised or subtracted cDNA libraries. Unlike whole genome sequencing, where multiple sequencing of each segment is the norm, ESTs are single pass reads of unverified quality that may contain base-calling and other errors. Additionally an EST may often only provide information on a partial segment of an entire cDNA. Finally, analysis of EST datasets can be overwhelming due to the sheer number of sequences involved.To address issues of redundancy, quality and data handling, EST clusteri
On the Origin of Risk Sensitivity: the Energy Budget Rule Revisited
Ik Soo Lim,Peter Wittek,John Parkinson
Quantitative Biology , 2015, DOI: 10.1016/j.anbehav.2015.09.007
Abstract: The risk-sensitive foraging theory formulated in terms of the (daily) energy budget rule has been influential in behavioural ecology as well as other disciplines. Predicting risk-aversion on positive budgets and risk-proneness on negative budgets, however, the budget rule has recently been challenged both empirically and theoretically. In this paper, we critically review these challenges as well as the original derivation of the budget rule and propose a `gradual' budget rule, which is normatively derived from a gradual nature of risk sensitivity and encompasses the conventional budget rule as a special case. The gradual budget rule shows that the conventional budget rule holds when the expected reserve is close enough to a threshold for overnight survival, selection pressure being significant. The gradual view also reveals that the conventional budget rule does not need to hold when the expected reserve is not close enough to the threshold, selection pressure being insignificant. The proposed gradual budget rule better fits the empirical findings including those that used to challenge the conventional budget rule.
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