739 research outputs found

    Comparative inhibition by substrate analogues 3-methoxy- and 3-hydroxydesaminokynurenine and an improved 3 step purification of recombinant human kynureninase.

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    BACKGROUND: Kynureninase is a key enzyme on the kynurenine pathway of tryptophan metabolism. One of the end products of the pathway is the neurotoxin quinolinic acid which appears to be responsible for neuronal cell death in a number of important neurological diseases. This makes kynureninase a possible therapeutic target for diseases such as Huntington's, Alzheimer's and AIDS related dementia, and the development of potent inhibitors an important research aim. RESULTS: Two new kynurenine analogues, 3-hydroxydesaminokynurenine and 3-methoxydesaminokynurenine, were synthesised as inhibitors of kynureninase and tested on the tryptophan-induced bacterial enzyme from Pseudomonas fluorescens, the recombinant human enzyme and the rat hepatic enzyme. They were found to be mixed inhibitors of all three enzymes displaying both competitive and non competitive inhibition. The 3-hydroxy derivative gave low K(i )values of 5, 40 and 100 nM respectively. An improved 3-step purification scheme for recombinant human kynureninase was also developed. CONCLUSION: For kynureninase from all three species the 2-amino group was found to be crucial for activity whilst the 3-hydroxyl group played a fundamental role in binding at the active site presumably via hydrogen bonding. The potency of the various inhibitors was found to be species specific. The 3-hydroxylated inhibitor had a greater affinity for the human enzyme, consistent with its specificity for 3-hydroxykynurenine as substrate, whilst the methoxylated version yielded no significant difference between bacterial and human kynureninase. The modified purification described is relatively quick, simple and cost effective

    Semantic fluency in deaf children who use spoken and signed language in comparison with hearing peers

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    BACKGROUND: Deafness has an adverse impact on children's ability to acquire spoken languages. Signed languages offer a more accessible input for deaf children, but because the vast majority are born to hearing parents who do not sign, their early exposure to sign language is limited. Deaf children as a whole are therefore at high risk of language delays. AIMS: We compared deaf and hearing children's performance on a semantic fluency task. Optimal performance on this task requires a systematic search of the mental lexicon, the retrieval of words within a subcategory and, when that subcategory is exhausted, switching to a new subcategory. We compared retrieval patterns between groups, and also compared the responses of deaf children who used British Sign Language (BSL) with those who used spoken English. We investigated how semantic fluency performance related to children's expressive vocabulary and executive function skills, and also retested semantic fluency in the majority of the children nearly 2 years later, in order to investigate how much progress they had made in that time. METHODS & PROCEDURES: Participants were deaf children aged 6-11 years (N = 106, comprising 69 users of spoken English, 29 users of BSL and eight users of Sign Supported English-SSE) compared with hearing children (N = 120) of the same age who used spoken English. Semantic fluency was tested for the category 'animals'. We coded for errors, clusters (e.g., 'pets', 'farm animals') and switches. Participants also completed the Expressive One-Word Picture Vocabulary Test and a battery of six non-verbal executive function tasks. In addition, we collected follow-up semantic fluency data for 70 deaf and 74 hearing children, nearly 2 years after they were first tested. OUTCOMES & RESULTS: Deaf children, whether using spoken or signed language, produced fewer items in the semantic fluency task than hearing children, but they showed similar patterns of responses for items most commonly produced, clustering of items into subcategories and switching between subcategories. Both vocabulary and executive function scores predicted the number of correct items produced. Follow-up data from deaf participants showed continuing delays relative to hearing children 2 years later. CONCLUSIONS & IMPLICATIONS: We conclude that semantic fluency can be used experimentally to investigate lexical organization in deaf children, and that it potentially has clinical utility across the heterogeneous deaf population. We present normative data to aid clinicians who wish to use this task with deaf children

    Field experiments with wild primates reveal no consistent dominance-based bias in social learning

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    Directed social learning suggests that information flows through social groups in a nonrandom way, with individuals biased to obtain information from certain conspecifics. A bias to copy the behaviour of more dominant individuals has been demonstrated in captive chimpanzees, Pan troglodytes, but has yet to be studied in any wild animal population. To test for this bias using a field experiment, one dominant and one low-ranking female in each of three groups of wild vervet monkeys, Chlorocebus aethiops pygerythrus, was trained on alternative methods of opening an 'artificial fruit'. Following 100 demonstrations from each model, fruits that could be opened either way were presented to each group and all openings were recorded. Overall, the dominant females were not attended to more than low-ranking females during the demonstrations, nor were their methods preferentially used in the test phase. We conclude that these monkeys show no overall bias to copy high-ranking models that would lead to a high-ranking model's behaviour becoming more prevalent in the group than a behaviour demonstrated by a low-ranking model. However, by contrast, there were significant effects of observer monkeys' rank and sex upon the likelihood they would match the dominant model. Additionally we found that the dominant models were more likely to stick to their initially learned method than were low-ranking model

    Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells

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    Scope In vitro and in vivo studies suggest that dietary anthocyanins modulate cardiovascular disease risk; however, given anthocyanins extensive metabolism, it is likely that their degradation products and conjugated metabolites are responsible for this reported bioactivity. Methods and results Human vascular endothelial cells were stimulated with either oxidized LDL (oxLDL) or cluster of differentiation 40 ligand (CD40L) and cotreated with cyanidin-3-glucoside and 11 of its recently identified metabolites, at 0.1, 1, and 10 μM concentrations. Protein and gene expression of IL-6 and VCAM-1 was quantified by ELISA and RT-qPCR. In oxLDL-stimulated cells the parent anthocyanin had no effect on IL-6 production, whereas numerous anthocyanin metabolites significantly reduced IL-6 protein levels; phase II conjugates of protocatechuic acid produced the greatest effects (>75% reduction, p ≤ 0.05). In CD40L-stimulated cells the anthocyanin and its phase II metabolites reduced IL-6 protein production, where protocatechuic acid-4-sulfate induced the greatest reduction (>96% reduction, p ≤ 0.03). Similarly, the anthocyanin and its metabolites reduced VCAM-1 protein production, with ferulic acid producing the greatest effect (>65% reduction, p ≤ 0.04). Conclusion These novel data provide evidence to suggest that anthocyanin metabolites are bioactive at physiologically relevant concentrations and have the potential to modulate cardiovascular disease progression by altering the expression of inflammatory mediators

    Registration of ovarian cancer in England and Wales

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    Cambrian, Ordovician and Silurian non-stromatoporoid Porifera

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    The Cambrian, Ordovician and Silurian distributions of non-stromatoporoid sponges are reviewed. The earliest Cambrian faunas contain mostly hexactinellids, with protomonaxonids dominating middle Cambrian assemblages. There are no obvious palaeobiogeographical patterns, with many genera being found widely. Vauxiids, lithistids and heteractinids are apparently confined to low latitudes, but this may be due to a poor fossil record. Most known Ordovician faunas are from low latitudes, although some high-latitude faunas are known, which contain reticulosan hexactinellids and protomonaxonids. There is some division of faunas within Laurentia, into eastern and western provinces, with the western assemblage extending across low northern latitudes during the Late Ordovician. During the Silurian Period, sponge diversity was very low during the Llandovery Epoch, probably partly owing to lack of habitat for taxa restricted to carbonate facies, and also because of sampling bias. There was a dramatic increase in diversity through the Silurian Period, mostly owing to an apparent diversification in the demosponges; however, there are many ghost lineages, indicating that their fossil record is poorly known. Non-lithistid sponges are very poorly known, with few recorded outside Euramerica. The currently available data for Early Palaeozoic sponges are too incomplete to allow any reliable palaeobiogeographical inferences.Fil: Muir, Lucy A.. Chinese Academy of Sciences. Nanjing Institute of Geology and Palaeontology; ChinaFil: Botting, Joshep P.. Chinese Academy of Sciences. Nanjing Institute of Geology and Palaeontology; ChinaFil: Carrera, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Ciencias de la Tierra; ArgentinaFil: Beresi, Matilde Sylvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Científico Tecnológico Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentin
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