An Empirical Study of the Use of Relevance Information in Inductive Logic Programming

Srinivasan, A., King, R. D. and Bain, M.E. (2003) An Empirical Study of the Use of Relevance Information in Inductive Logic Programming. Journal of Machine Learning Research. 4(Jul):369-383

The relevance and admissibility of prior sexual history with the defendant in sexual offence cases

Kibble, N, ?The Relevance and Admissibility of Prior Sexual History with the Defendant in Sexual Offence Cases? (2001) 32 Cambrian Law Review 27-63 (cited with approval by HL in R v A(2) [2002] AC 45) RAE2008

Judicial Perspectives on the Operation of s.41 and the Relevance and Admissibility of Prior Sexual History Evidence: Four Scenarios

Judicial Perspectives on the Operation of s.41 and the Relevance and Admissibility of Prior Sexual History Evidence: Four scenarios. N.Kibble. Crim.L.R. 2005 190. RAE2008

Predicting interpretability of metabolome models based on behavior, putative identity, and biological relevance of explanatory signals

Enot, D. P., Beckmann, M., Overy, D., Draper, J. (2006). Predicting interpretability of metabolome models based on behavior, putative identity, and biological relevance of explanatory signals. Proceedings of the National Academy of Sciences of the USA, 103(40), 14865-14870. Sponsorship: BBSRC RAE2008

Image Digestion and Relevance Feedback in the ImageRover WWW Search Engine

ImageRover is a search by image content navigation tool for the world wide web. The staggering size of the WWW dictates certain strategies and algorithms for image collection, digestion, indexing, and user interface. This paper describes two key components of the ImageRover strategy: image digestion and relevance feedback. Image digestion occurs during image collection; robots digest the images they find, computing image decompositions and indices, and storing this extracted information in vector form for searches based on image content. Relevance feedback occurs during index search; users can iteratively guide the search through the selection of relevant examples. ImageRover employs a novel relevance feedback algorithm to determine the weighted combination of image similarity metrics appropriate for a particular query. ImageRover is available and running on the web site.

Max Stirner's relevance to contemporary philosophy: a critical analysis

The aim of this dissertation is to revive the 19th-century thinker Max Stirner’s thought through a critical reexamination of his mistaken legacy as a ‘political’ thinker. The reading of Stirner that I present is one of an ontological thinker, spurred on as much—if not more—by the contents of Hegel’s Phenomenology of Spirit as it is the radical roots that Hegel unintentionally planted. In the first chapter, the role of language in Stirner’s thought is examined, and the problems to which his conception of language seem to give rise are addressed. The second chapter looks at Stirner’s purportedly ‘anarchistic’ politics and finds the ‘anarchist’ reading of Stirner misguided. Rather than being a ‘political’ anarchist, it is argued that we ought to understand Stirner as advocating a sort of ‘ontological’ anarchism in which the very existence of authority is questioned. In the third chapter, I look at the political ramifications of Stirner’s ontology as well as the critique of liberalism contained within it, and argue that the politics implicit in his philosophy shares more in common with the tradition of political realism than it does anarchism. The fourth chapter is dedicated to an examination of Stirner’s anti-humanism, which is concluded to be much different than the ‘anti-humanisms’ associated with other, more famous thinkers, such as Foucault and Heidegger. In the fifth and final chapter, I provide an answer to the question(s) of how, if, and to what extent Friedrich Nietzsche was influenced by Stirner. It is concluded that the complete lack of evidence that Nietzsche ever read Stirner is proof enough to dismiss accusations of plagiarism on Nietzsche’s part, thus emphasizing the originality and singularity of both thinkers.

The role of mitogen activated protein kinase phosphatase-1 in neurotoxic and inflammatory-induced changes in the development of midbrain dopaminergic neurons: relevance to Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by the loss of midbrain dopaminergic neurons from the substantia nigra pars compacta(SNpc), which results in motor, cognitive and psychiatric symptoms. Evidence supports a role for the mitogen-activated protein kinase p38 in the demise of dopaminergic neurons, while mitogen-activated protein kinase phosphatase-1 (MKP-1), which negatively regulates p38 activity, has not yet been investigated in this context. Inflammation may also be associated with the neuropathology of PD due to evidence of increased levels of proinflammatory cytokines such as interleukin-1β (IL-1β) within the SNpc. Because of the specific loss of dopaminergic neurons in a discreet region of the brain, PD is considered a suitable candidate for cell replacement therapy but challenges remain to optimise dopaminergic cell survival and morphological development. The present thesis examined the role of MKP-1 in neurotoxic and inflammatory-induced changes in the development of midbrain dopaminergic neurons. We show that MKP-1 is expressed in dopaminergic neurons cultured from embryonic day (E) 14 rat ventral mesencephalon (VM). Inhibition of dopaminergic neurite growth induced by treatment of rat VM neurons with the dopaminergic neurotoxin 6- hydroxydopamine (6-OHDA) is mediated by p38, and is concomitant with a significant and selective decrease in MKP-1 expression in these neurons. Dopaminergic neurons transfected to overexpress MKP-1 displayed a more complex morphology and contributed to neuroprotection against the effects of 6-OHDA. Therefore, MKP-1 expression can promote the growth and elaboration of dopaminergic neuronal processes and can help protect them from the neurotoxic effects of 6-OHDA. Neural precursor cells (NPCs) have emerged as promising alternative candidates to fetal VM for cell replacement strategies in PD. Here we show that phosphorylated (and thus activated) p38 and MKP-1 are expressed at basal levels in untreated E14 rat VM NPCs (nestin, DCX, GFAP and DAT-positive cells) following proliferation as well as in their differentiated progeny (DCX, DAT, GFAP and βIII-tubulin) in vitro. Challenge with 6-OHDA or IL-1β changed the expression of endogenous phospho-p38 and MKP-1 in these cells in a time-dependent manner, and so the dynamic balance in expression may mediate the detrimental effects of neurotoxicity and inflammation in proliferating and differentiating NPCs. We demonstrate that there was an up-regulation in MKP-1 mRNA expression in adult rat midbrain tissue 4 days post lesion in two rat models of PD; the 6-OHDA medial forebrain bundle (MFB) model and the four-site 6-OHDA striatal lesion model. This was concomitant with a decrease in tyrosine hydroxylase (TH) mRNA expression at 4 and 10 days post-lesion in the MFB model and 10 and 28 days post-lesion in the striatal lesion model. There was no change in mRNA expression of the pro-apoptotic gene, bax and the anti-apoptotic gene, bcl-2 in the midbrain and striatum. These data suggest that the early and transient upregulation of MKP-1 mRNA in the midbrain at 4 days post-6-OHDA administration may be indicative of an attempt by dopaminergic neurons in the midbrain to protect against the neurotoxic effects of 6-OHDA at later time points. Collectively, these findings show that MKP-1 is expressed by developing and adult dopaminergic neurons in the midbrain, and can promote their morphological development. MKP-1 also exerts neuroprotective effects against dopaminergic neurotoxins in vitro, and its expression in dopaminergic neurons can be modulated by inflammatory and neurotoxic insults both in vitro and in vivo. Thus, these data contribute to the information needed to develop therapeutic strategies for protecting midbrain dopaminergic neurons in the context of PD.

The relevance of bacterial isoprenoid biosynthetic pathways for host-microbe interactions

This thesis was undertaken to investigate the relevance of two bacterial isoprenoid biosynthetic pathways (Mevalonate (MVAL) and 2-C-methyl-D-erythritol 4-phosphate (MEP)) for host-microbe interactions. We determined a significant reduction in microbial diversity in the murine gut microbiota (by next generation sequencing) following oral administration of a common anti-cholesterol drug Rosuvastatin (RSV) that targets mammalian and bacterial HMG-CoA reductase (HMG-R) for inhibition of MVAL formation. In tandem we identified significant hepatic and intestinal off-target alterations to the murine metabolome indicating alterations in inflammation, bile acid profiles and antimicrobial peptide synthesis with implications on community structure of the gastrointestinal microbiota in statin-treated animals. However we found no effect on local Short Chain Fatty Acid biosynthesis (metabolic health marker in our model). We demonstrated direct inhibition of bacterial growth in-vitro by RSV which correlated with reductions in bacterial MVAL formation. However this was only at high doses of RSV. Our observations demonstrate a significant RSV-associated impact on the gut microbiota prompting similar human analysis. Successful deletion of another MVAL pathway enzyme (HMG-CoA synthase (mvaS)) involved in Listeria monocytogenes EGDe isoprenoid biosynthesis determined that the enzyme is non-essential for normal growth and in-vivo pathogenesis of this pathogen. We highlight potential evidence for alternative means of synthesis of the HMG-CoA substrate that could render mvaS activity redundant under our test conditions. Finally, we showed by global gene expression analysis (Massive Analysis of cDNA Ends (MACE RNA-seq) a significant role for the penultimate MEP pathway metabolite (E)-4-hydroxy-3-methyl-2-but-2-enyl pyrophosphate (HMBPP) in significant up regulation of genes of immunity and antigen presentation in THP-1 cells at nanomolar levels. We infected THP-1 cells with wild type or HMBPP under/over-producing L. monoctyogenes EGDe mutants and determined subtle effects of HMBPP upon overall host responses to Listeria infection. Overall our findings provide greater insights regarding bacterial isoprenoid biosynthetic pathways for host-microbe/microbe-host dialogue.

Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes.

-Transgenic mouse models have been developed to manipulate beta-adrenergic receptor (betaAR) signal transduction. Although several of these models have altered betaAR subtypes, the specific functional sequelae of betaAR stimulation in murine heart, particularly those of beta2-adrenergic receptor (beta2AR) stimulation, have not been characterized. In the present study, we investigated effects of beta2AR stimulation on contraction, [Ca2+]i transient, and L-type Ca2+ currents (ICa) in single ventricular myocytes isolated from transgenic mice overexpressing human beta2AR (TG4 mice) and wild-type (WT) littermates. Baseline contractility of TG4 heart cells was increased by 3-fold relative to WT controls as a result of the presence of spontaneous beta2AR activation. In contrast, beta2AR stimulation by zinterol or isoproterenol plus a selective beta1-adrenergic receptor (beta1AR) antagonist CGP 20712A failed to enhance the contractility in TG4 myocytes, and more surprisingly, beta2AR stimulation was also ineffective in increasing contractility in WT myocytes. Pertussis toxin (PTX) treatment fully rescued the ICa, [Ca2+]i, and contractile responses to beta2AR agonists in both WT and TG4 cells. The PTX-rescued murine cardiac beta2AR response is mediated by cAMP-dependent mechanisms, because it was totally blocked by the inhibitory cAMP analog Rp-cAMPS. These results suggest that PTX-sensitive G proteins are responsible for the unresponsiveness of mouse heart to agonist-induced beta2AR stimulation. This was further corroborated by an increased incorporation of the photoreactive GTP analog [gamma-32P]GTP azidoanilide into alpha subunits of Gi2 and Gi3 after beta2AR stimulation by zinterol or isoproterenol plus the beta1AR blocker CGP 20712A. This effect to activate Gi proteins was abolished by a selective beta2AR blocker ICI 118,551 or by PTX treatment. Thus, we conclude that (1) beta2ARs in murine cardiac myocytes couple to concurrent Gs and Gi signaling, resulting in null inotropic response, unless the Gi signaling is inhibited; (2) as a special case, the lack of cardiac contractile response to beta2AR agonists in TG4 mice is not due to a saturation of cell contractility or of the cAMP signaling cascade but rather to an activation of beta2AR-coupled Gi proteins; and (3) spontaneous beta2AR activation may differ from agonist-stimulated beta2AR signaling.

A systematic review of the effect of dietary exposure that could be achieved through normal dietary intake on learning and performance of school-aged children of relevance to UK schools

The aim of the present review was to perform a systematic in-depth review of the best evidence from controlled trial studies that have investigated the effects of nutrition, diet and dietary change on learning, education and performance in school-aged children (4-18 years) from the UK and other developed countries. The twenty-nine studies identified for the review examined the effects of breakfast consumption, sugar intake, fish oil and vitamin supplementation and 'good diets'. In summary, the studies included in the present review suggest there is insufficient evidence to identify any effect of nutrition, diet and dietary change on learning, education or performance of school-aged children from the developed world. However, there is emerging evidence for the effects of certain fatty acids which appear to be a function of dose and time. Further research is required in settings of relevance to the UK and must be of high quality, representative of all populations, undertaken for longer durations and use universal validated measures of educational attainment. However, challenges in terms of interpreting the results of such studies within the context of factors such as family and community context, poverty, disease and the rate of individual maturation and neurodevelopment will remain. Whilst the importance of diet in educational attainment remains under investigation, the evidence for promotion of lower-fat, -salt and -sugar diets, high in fruits, vegetables and complex carbohydrates, as well as promotion of physical activity remains unequivocal in terms of health outcomes for all schoolchildren.