414 research outputs found

    An analysis of learning in weightless neural systems

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    This thesis brings together two strands of neural networks research - weightless systems and statistical learning theory - in an attempt to understand better the learning and generalisation abilities of a class of pattern classifying machines. The machines under consideration are n-tuple classifiers. While their analysis falls outside the domain of more widespread neural networks methods the method has found considerable application since its first publication in 1959. The larger class of learning systems to which the n-tuple classifier belongs is known as the set of weightless or RAM-based systems, because of the fact that they store all their modifiable information in the nodes rather than as weights on the connections. The analytical tools used are those of statistical learning theory. Learning methods and machines are considered in terms of a formal learning problem which allows the precise definition of terms such as learning and generalisation (in this context). Results relating the empirical error of the machine on the training set, the number of training examples and the complexity of the machine (as measured by the Vapnik- Chervonenkis dimension) to the generalisation error are derived. In the thesis this theoretical framework is applied for the first time to weightless systems in general and to n-tuple classifiers in particular. Novel theoretical results are used to inspire the design of related learning machines and empirical tests are used to assess the power of these new machines. Also data-independent theoretical results are compared with data-dependent results to explain the apparent anomalies in the n-tuple classifier's behaviour. The thesis takes an original approach to the study of weightless networks, and one which gives new insights into their strengths as learning machines. It also allows a new family of learning machines to be introduced and a method for improving generalisation to be applied.Open Acces

    NDE1 in the DISC1 pathway: interactions of schizophrenia-related proteins

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    The Disrupted-In-Schizophrenia 1 (DISC1) gene is one of the most established risk genes for psychiatric illness currently being studied, having originally been identified as being directly disrupted by a balanced chromosomal translocation that cosegregates with schizophrenia and other major mental illness a large Scottish family. The DISC1 protein is believed to act as a molecular scaffold within the cell, binding to a large number of other proteins. Three of these protein interactors, Phosphodiesterase 4B (PDE4B), Nuclear Distribution Factor E (Aspergillus nidulans)-homologue 1 (NDE1) and NDE-Like 1 (NDEL1) all have evidence implicating them as schizophrenia-related proteins in their own right. NDE1 and NDEL1 are highly similar proteins which are known to play cellular roles including microtubule function and mitosis. Their orthologues have also been shown to be important in neurodevelopment within the mouse brain. To date, most work in the literature has investigated NDEL1, with few focusing on NDE1. In the thesis, I first seek to establish a basic biology for NDE1 by the identification of splice variants expressed in the brain, establishing cellular localisation patterns within the cell and investigating NDE1 multimerisation. The relationship between NDE1 and NDEL1 is also investigated, with the two being found to form complexes together and to have partially over-lapping expression patterns within the cell. That NDE1 and DISC1 directly interact is confirmed. The relationship between NDE1 and PDE4B is then investigated, with the two proteins found to complex within the cell. Additionally, it is shown that NDE1 can be phosphorylated by protein kinase A (PKA). This kinase is cAMP dependant, and is thus indirectly regulated by the cAMP-degrading action of PDE4B protein. Attempts to map and analyse the effect of this phosphorylation on NDE1 are made

    The interaction of schizophrenia-related proteins DISC1 and NDEL1, in light of the newly identified domain structure of DISC1

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    DISC1 and NDEL1 are both key proteins in cortical neurodevelopment, which are each also implicated in the pathogenesis of mental illness. That the two proteins interact with each other in a functionally important manner is well established, but two distinct binding domains for NDEL1 on DISC1 have been proposed. A partial domain structure for DISC1 has recently been described, consisting of 4 structured regions referred to as “D,” “I,” “S” and “C” respectively, with one of the NDEL1 binding sites lying in the “C” region of DISC1. In light of this domain structure, it can be deduced that this site is the likely location at which NDEL1 binds, although the other proposed site (which lies in the DISC1 “I” and “S” regions) may indirectly impact on DISC1-NDEL1 interactions through determination of the oligomeric state of DISC1

    SYMPTOM SEVERITY IN SCHIZOPHRENIA PATIENTS WITH NPAS3, DYSBINDIN-1 AND/OR TRIOBP PROTEIN PATHOLOGY IN THEIR BLOOD SERUM: A PANSS-BASED FOLLOW UP STUDY

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    Background: It has been proposed that aggregation of specific proteins in the brain may be a pathological element in schizophrenia and other chronic disorders. Multiple such aggregating proteins have now been implicated through post mortem investigation, including NPAS3 (Neuronal PAS domain protein 3), dysbindin-1 (encoded by the DTNBP1, Dystrobrevin Binding Protein 1, gene) and TRIOBP (Trio-Binding Protein, multiple isoforms). While the presence of protein aggregates in the brain is interesting in terms of understanding pathology, it is impractical as a biomarker. These proteins were therefore investigated recently in blood serum of schizophrenia patients and controls, showing patients to have higher levels of NPAS3 in their serum generally. TRIOBP-1 and dysbindin-1 were also found in an insoluble state, implying aggregation, but did not clearly corresponding to disease state. Subject and methods: We revisit 47 of the originally recruited 50 patients with schizophrenia, all of whom are Croatian and aged between 18 and 72. We assessed their symptom specificity and severity using PANSS (the Positive and Negative Symptoms Scale), comparing those with NPAS3, insoluble dysbindin-1 and/or insoluble TRIOBP-1 in their blood serum to those lacking any such protein dysregulation. Results: The frequency of each individual potential protein pathology among these patients was too low for meaningful statistical analysis, however the 11 patients that displayed one or more of these pathologies (NPAS3, dysbindin-1, TRIOBP-1 and/or TRIOBP- 5/6) showed a subtle but significant increase in total PANSS scores compared to the 36 patients displaying none of the pathologies (p = 0.031), seemingly driven principally by increased scores on the general psychopathology scale. Conclusion: While the numbers of patients involved do not allow firm conclusions to be drawn at this time, this provides the first indication that disturbed proteostasis in blood serum, of proteins that aggregate in the brains of schizophrenia patients, may correlate with the severity of schizophrenia symptoms

    Education and training in radioecology during the EU-COMET project-successes and suggestions for the future

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    The 2014 Strategic Research Agenda (SRA) for Radioecology identified the key challenge in education and training (E&T) as being 'to maintain and develop a skilled workforce in Europe and world-wide, through university candidates and professionals trained within radioecology' since 'scientific research in radioecology and application of that knowledge ... requires scientists and workers with adequate competence and appropriate skills.' Radioecology is a multidisciplinary science and E&T is needed by both students and professionals within research, industry and radiation protection. In order to address these needs, the EU COMET project has developed an E&T web platform and arranged a number of field courses, training courses, PhD and MSc courses, refresher courses and workshops, drawing on the COMET consortium to assemble relevant experts. In addition, COMET has been engaged in discussions with stakeholders for more long-term solutions to maintain the sustainability of radioecology E&T after the end of the project. Despite much progress in some areas, many of the challenges outlined in the 2014 SRA remain, mainly due to the lack of sustainable dedicated funding. Future plans within the ALLIANCE radioecology platform and the CONCERT-European Joint Programme for the Integration of Radiation Protection Research must urgently address this lack of sustainability if radioecological competence is to be maintained in Europe

    MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

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    Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology
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