502 research outputs found

    Neural Signatures of Prediction Errors in a Decision-Making Task are Modulated by Action Execution Failures

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    Decisions must be implemented through actions, and actions are prone to error. As such, when an expected outcome is not obtained, an individual should be sensitive to not only whether the choice itself was suboptimal but also whether the action required to indicate that choice was executed successfully. The intelligent assignment of credit to action execution versus action selection has clear ecological utility for the learner. To explore this, we used a modified version of a classic reinforcement learning task in which feedback indicated whether negative prediction errors were, or were not, associated with execution errors. Using fMRI, we asked if prediction error computations in the human striatum, a key substrate in reinforcement learning and decision making, are modulated when a failure in action execution results in the negative outcome. Participants were more tolerant of non-rewarded outcomes when these resulted from execution errors versus when execution was successful, but reward was withheld. Consistent with this behavior, a model-driven analysis of neural activity revealed an attenuation of the signal associated with negative reward prediction errors in the striatum following execution failures. These results converge with other lines of evidence suggesting that prediction errors in the mesostriatal dopamine system integrate high-level information during the evaluation of instantaneous reward outcomes

    Oceanographic conditions associated with white shark (Carcharodon carcharias) habitat use along eastern Australia

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    Management of species with wide-ranging migrations is a complex issue, made more challenging when the species is both protected and poses a risk to humans. Understanding the oceanic conditions associated with shark habitat use can help develop mitigation strategies or warning systems that meet both conservation and human safety objectives. Using satellite tracks from 77 juvenile and sub-adult white sharks tagged over 10 yr, we modelled individual movement patterns using hidden Markov models and applied generalised additive (mixed) models to explore correlations between movement patterns (presence−absence, habitat selection and behavioural state) and oceanographic and bathymetric variables. White sharks used the whole of the continental shelf, down to depths of 350 m on the continental slope. Sharks were present over a wide range of sea surface temperatures (SSTs; 10−27°C), with the highest probability of occurring at ~20°C. However, the number of average daily tag positions was greatest when SST was between 14 and 18°C, and sharks were more likely to exhibit area-restricted movement when SST was between ~19 and 23°C. Sharks were more likely to be present and selected habitats in productive areas with moderate to high surface chl a concentrations as well as thermal and productivity fronts. Although mesoscale eddies did not influence the likelihood of individuals being present in an area, there was a higher density of sharks in cold-core eddies compared to warm-core eddies. This study indicates that white shark presence and dispersal may be linked, perhaps via prey distribution, to oceanic conditions, potentially assisting development of suitable shark bite mitigation strategies

    The Imprint of Galaxy Formation on X-ray Clusters

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    It is widely believed that structure in the Universe evolves hierarchically, as primordial density fluctuations, amplified by gravity, collapse and merge to form progressively larger systems. The structure and evolution of X-ray clusters, however, seems at odds with this hierarchical scenario for structure formation. Poor clusters and groups, as well as most distant clusters detected to date, are substantially fainter than expected from the tight relations between luminosity, temperature and redshift predicted by these models. Here we show that these discrepancies arise because, near the centre, the entropy of the hot, diffuse intracluster medium (ICM) is higher thaachievablethroughgravitationalcollapse,indicatingsubstantialnon−gravitationalheatingoftheICM.Weestimatethisexcessentropyforthefirsttime,andarguethatitrepresentsarelicoftheenergeticwindsthroughwhichforminggalaxiespollutedtheICMwithmetals.Energetically,thisisonl achievable through gravitational collapse, indicating substantial non-gravitational heating of the ICM. We estimate this excess entropy for the first time, and argue that it represents a relic of the energetic winds through which forming galaxies polluted the ICM with metals. Energetically, this is onl possible if the ICM is heated at modest redshift (z \ltsim 2) but prior to cluster collapse, indicating that the formation of galaxies precedes that of clusters and that most clusters have been assembled very recently.Comment: 5 pages, plus 2 postscript figures (one in colour), accepted for publication in Natur

    The yield of essential oils in Melaleuca alternifolia (Myrtaceae) is regulated through transcript abundance of genes in the MEP pathway

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    Medicinal tea tree (Melaleuca alternifolia) leaves contain large amounts of an essential oil, dominated by monoterpenes. Several enzymes of the chloroplastic methylerythritol phosphate (MEP) pathway are hypothesised to act as bottlenecks to the production of monoterpenes. We investigated, whether transcript abundance of genes encoding for enzymes of the MEP pathway were correlated with foliar terpenes in M. alternifolia using a population of 48 individuals that ranged in their oil concentration from 39 -122 mg x g DM(-1). Our study shows that most genes in the MEP pathway are co-regulated and that the expression of multiple genes within the MEP pathway is correlated with oil yield. Using multiple regression analysis, variation in expression of MEP pathway genes explained 87% of variation in foliar monoterpene concentrations. The data also suggest that sesquiterpenes in M. alternifolia are synthesised, at least in part, from isopentenyl pyrophosphate originating from the plastid via the MEP pathway

    Altered DNA methylation associated with a translocation linked to major mental illness

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    Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 individuals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers (n = 17) were compared to related non-carriers (n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10, have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in individuals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions

    Safety and Clinical Outcome of Thrombolysis in Ischaemic Stroke Using a Perfusion CT Mismatch between 3 and 6 Hours

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    It may be possible to thrombolyse ischaemic stroke (IS) patients up to 6 h by using penumbral imaging. We investigated whether a perfusion CT (CTP) mismatch can help to select patients for thrombolysis up to 6 h.A cohort of 254 thrombolysed IS patients was studied. 174 (69%) were thrombolysed at 0-3 h by using non-contrast CT (NCCT), and 80 (31%) at 3-6 h (35 at 3-4.5 h and 45 at 4.5-6 h) by using CTP mismatch criteria. Symptomatic intracerebral haemorrhage (SICH), the mortality and the modified Rankin Score (mRS) were assessed at 3 months. Independent determinants of outcome in patients thrombolysed between 3 and 6 h were identified.The baseline characteristics were comparable in the two groups. There were no differences in SICH (3% v 4%, p = 0.71), any ICH (7% v 9%, p = 0.61), or mortality (16% v 9%, p = 0.15) or mRS 0-2 at 3 months (55% v 54%, p = 0.96) between patients thrombolysed at 0-3 h (NCCT only) or at 3-6 h (CTP mismatch). There were no significant differences in outcome between patients thrombolysed at 3-4.5 h or 4.5-6 h. The NIHSS score was the only independent determinant of a mRS of 0-2 at 3 months (OR 0.89, 95% CI 0.82-0.97, p = 0.007) in patients treated using CTP mismatch criteria beyond 3 h.The use of a CTP mismatch model may help to guide thrombolysis decisions up to 6 h after IS onset

    The complete sequence of the Acacia ligulata chloroplast genome reveals a highly divergent clpP1 gene

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    Legumes are a highly diverse angiosperm family that include many agriculturally important species. To date, 21 complete chloroplast genomes have been sequenced from legume crops confined to the Papilionoideae subfamily. Here we report the first chloroplast genome from the Mimosoideae, Acacia ligulata, and compare it to the previously sequenced legume genomes. The A. ligulata chloroplast genome is 158,724 bp in size, comprising inverted repeats of 25,925 bp and single-copy regions of 88,576 bp and 18,298 bp. Acacia ligulata lacks the inversion present in many of the Papilionoideae, but is not otherwise significantly different in terms of gene and repeat content. The key feature is its highly divergent clpP1 gene, normally considered essential in chloroplast genomes. In A. ligulata, although transcribed and spliced, it probably encodes a catalytically inactive protein. This study provides a significant resource for further genetic research into Acacia and the Mimosoideae. The divergent clpP1 gene suggests that Acacia will provide an interesting source of information on the evolution and functional diversity of the chloroplast Clp protease comple

    Leishmania major Survival in Selective Phlebotomus papatasi Sand Fly Vector Requires a Specific SCG-Encoded Lipophosphoglycan Galactosylation Pattern

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    Phlebotomine sand flies that transmit the protozoan parasite Leishmania differ greatly in their ability to support different parasite species or strains in the laboratory: while some show considerable selectivity, others are more permissive. In “selective” sand flies, Leishmania binding and survival in the fly midgut typically depends upon the abundant promastigote surface adhesin lipophosphoglycan (LPG), which exhibits species- and strain-specific modifications of the dominant phosphoglycan (PG) repeat units. For the “selective” fly Phlebotomus papatasi PpapJ, side chain galactosyl-modifications (scGal) of PG repeats play key roles in parasite binding. We probed the specificity and properties of this scGal-LPG PAMP (Pathogen Associated Molecular Pattern) through studies of natural isolates exhibiting a wide range of galactosylation patterns, and of a panel of isogenic L. major engineered to express similar scGal-LPG diversity by transfection of SCG-encoded ÎČ1,3-galactosyltransferases with different activities. Surprisingly, both ‘poly-scGal’ and ‘null-scGal’ lines survived poorly relative to PpapJ-sympatric L. major FV1 and other ‘mono-scGal’ lines. However, survival of all lines was equivalent in P. duboscqi, which naturally transmit L. major strains bearing ‘null-scGal’-LPG PAMPs. We then asked whether scGal-LPG-mediated interactions were sufficient for PpapJ midgut survival by engineering Leishmania donovani, which normally express unsubstituted LPG, to express a ‘PpapJ-optimal’ scGal-LPG PAMP. Unexpectedly, these “L. major FV1-cloaked” L. donovani-SCG lines remained unable to survive within PpapJ flies. These studies establish that midgut survival of L. major in PpapJ flies is exquisitely sensitive to the scGal-LPG PAMP, requiring a specific ‘mono-scGal’ pattern. However, failure of ‘mono-scGal’ L. donovani-SCG lines to survive in selective PpapJ flies suggests a requirement for an additional, as yet unidentified L. major-specific parasite factor(s). The interplay of the LPG PAMP and additional factor(s) with sand fly midgut receptors may determine whether a given sand fly host is “selective” or “permissive”, with important consequences to both disease transmission and the natural co-evolution of sand flies and Leishmania

    Gain of DNA methylation is enhanced in the absence of CTCF at the human retinoblastoma gene promoter

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    <p>Abstract</p> <p>Background</p> <p>Long-term gene silencing throughout cell division is generally achieved by DNA methylation and other epigenetic processes. Aberrant DNA methylation is now widely recognized to be associated with cancer and other human diseases. Here we addressed the contribution of the multifunctional nuclear factor CTCF to the epigenetic regulation of the human <it>retinoblastoma </it>(<it>Rb</it>) gene promoter in different tumoral cell lines.</p> <p>Methods</p> <p>To assess the DNA methylation status of the <it>Rb </it>promoter, genomic DNA from stably transfected human erythroleukemic K562 cells expressing a <it>GFP </it>reporter transgene was transformed with sodium bisulfite, and then PCR-amplified with modified primers and sequenced. Single- and multi-copy integrants with the CTCF binding site mutated were isolated and characterized by Southern blotting. Silenced transgenes were reactivated using 5-aza-2'-deoxycytidine and Trichostatin-A, and their expression was monitored by fluorescent cytometry. <it>Rb </it>gene expression and protein abundance were assessed by RT-PCR and Western blotting in three different glioma cell lines, and DNA methylation of the promoter region was determined by sodium bisulfite sequencing, together with CTCF dissociation and methyl-CpG-binding protein incorporation by chromatin immunoprecipitation assays.</p> <p>Results</p> <p>We found that the inability of CTCF to bind to the <it>Rb </it>promoter causes a dramatic loss of gene expression and a progressive gain of DNA methylation.</p> <p>Conclusions</p> <p>This study indicates that CTCF plays an important role in maintaining the <it>Rb </it>promoter in an optimal chromatin configuration. The absence of CTCF induces a rapid epigenetic silencing through a progressive gain of DNA methylation. Consequently, CTCF can now be seen as one of the epigenetic components that allows the proper configuration of tumor suppressor gene promoters. Its aberrant dissociation can then predispose key genes in cancer cells to acquire DNA methylation and epigenetic silencing.</p
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