Adverse childhood experiences (ACEs) include physical or emotional abuse, neglect, and domestic violence. The World Health Organisation describes ACEs as the commonest and most intense childhood stressors. About half of us may endure at least one, but children exposed to several are likely to have more health problems later in life, including chronic pain. There are links between exposure to multiple ACEs and social deprivation and the likelihood of ACE exposure is higher for boys, and for children of a young mother. Although there is good evidence that ACEs contribute to health inequalities, there is no widespread screening or systematic approach to reducing long term harms. Reasons for this include limitations in existing assessment approaches, and little consideration of other factors that might increase vulnerability. Our CAPE consortium will bring together people from a wide range of backgrounds- such as scientists, people with lived experience of ACE and chronic pain, clinical researchers, epidemiologists and psychologists. We will use an inclusive approach to integrate biological, psychological, social and cultural factors to understand the impact of ACE on chronic pain and how people respond to treatment. There are 5 related work packages: 1. We aim to develop a questionnaire-based assessment that captures ACEs. We will analyse current approaches to see which ones work best. Alongside this we will use people's first-hand accounts, to ensure that lived experiences of ACEs and chronic pain, are accurately reflected in our approach. Working with patient partners we will bring together this information to develop and test a new ACE questionnaire (the CAPE ACEQ). 2. The CAPE ACEQ will be used to enrich pre-existing data in large scale population research datasets, (e.g. UK Biobank). We will also collect data about pain and social interactions (adult relationships). We will link this to prescribing, health records (including mental health) to identify psychosocial factors that create vulnerability to chronic pain and adverse responses to treatment in those exposed to ACEs. We will examine whether the increased burden of chronic pain, which disproportionately affects those exposed to multiple ACEs, leads to higher levels of opioid prescribing and associated adverse events observed in deprived communities. 3. We will collect similar data on pain, its impact (mood, sleep, fatigue etc), ACEs, health and social factors from a large group of young patients suffering from a condition called juvenile idiopathic arthritis (JIA), who attend a specialist unit in London. We will be able to understand what factors lead to different pain routes and outcomes in these young people. 4. We will use brain imaging data from the existing population studies and new brain imaging from the young JIA group, to establish whether there are changes in brain structure and/or function that may be associated with the development of poor pain and prescribing outcomes in those exposed to ACEs. 5. We will seek biological markers of vulnerability or resilience to chronic pain and treatment in those exposed to multiple ACEs. For this we will study genetic factors, and test properties of brain cells, from donated samples. Participants in a population study called the Lothian Birth Cohort will be asked about their exposure to ACEs. Many have consented to donate brain tissue post-mortem and have already provided blood for the production of pluripotent stem cells. These special cells will be differentiated to form brain cells. We anticipate that high quality evidence linking ACEs to chronic pain and treatment outcomes, combined with knowledge of mental health and social support, will provide a basis to develop individualised approaches to pain management and identify public health interventions to improve outcomes.

The primary aim of this project is to develop a simulation of the processes involved in solving the following problem: how to select, based on the agent's knowledge and representations of the world, one object from several, grasp the object and use it in an appropriate manner. This mundane activity in fact requires the simultaneous solution of several deep problems at various levels. The agent's visual system must represent potential target objects, the target must be selected based on task instructions or the agent's knowledge of the functions of the represented objects, and the hand (in this case) must be moved to the target and shaped so as to grip it in a manner appropriate for its use. We propose to develop a robotic simulation model inspired by recent theories of embodied cognition, in which the vision, action and semantic systems are linked together, in a dynamic and mutually interactive manner, within a connectionist architecture. Human experimental work will constrain the temporal and dynamic properties of the system in an effort to develop a psychologically plausible model of embodied selection for action. As much of the cognitive mechanisms leading to the integration between action and vision for actions such as object assembly tasks are not fully known, new empirical studies in this project will also improve our insight of these embodied cognitive dynamics. New experiments and the use of the embodied cognitive model will also be used to further our understanding of language and cognition integration e.g. by providing further predictions and insights on the dynamics of language and action knowledge in object representation.This is an interdisciplinary project which involves expertise and methodologies from cognitive psychology, motor control, and computational/robotics modelling. The interdisciplinary nature of the project and the design and experimentation of cognitive agents make the project highly relevant to the Cognitive Systems Foresight programmeBehavioural studies, as proposed here, will be based on the eye-tracking methodology. This permits the identification of the time-course of visuo-attentional processes in action and language processing and will provide converging evidence from stimulus-response compatibility studies on object selection. Eye tracking data will also be used to constrain the behavioural and attentional strategies used by simulated cognitive robots during tasks involving object naming and selection. In eye-tracking experiments we will show arrays of novel objects and study three levels of action representation. At the encoding level, we manipulate the location and onset time of a visual detection probe in this array to reveal how observers attend and prepare their actions (Fischer et al., in press). At the representational/linguistic level, we present auditory object names and register the observer's eye movements towards the named objects (visual world paradigm, e.g. Altmann & Kamide, 2004). Linguistic manipulations, such as using phonological competitors ( candle-candy ), reveal the time course of the interplay between covert and overt attention and the relative strength of top-down (linguistic) vs bottom-up visual control over action prediction. Finally, at the execution level, we instruct participants to pick up the named object and record their overt manual responses (e.g., Chambers et al., 2002, 2004). Orthogonal to these three levels of embodiment, we gradually associate each novel object with a particular name and manual response, and we design object arrays with congruent and incongruent response requirements. This learning approach enables us to track embodied concept acquisition and its implications for action control, separately at the encoding, linguistic/representational, and execution level.

The majority of plant genes contain intervening sequences (introns). When a gene is turned on (transcribed), the DNA code is copied into a molecule of RNA called precursor messenger RNA (pre-mRNA). Intron sequences are removed from pre-mRNA by the process of splicing which joins the coding regions of genes (exons) together. The spliced mRNA is then translated into a protein. In many cases, in both plants and animals, pre-mRNAs can be spliced in different ways to generate different mRNAs / this is termed alternative splicing (AS). The alternative mRNAs produced can encode different proteins with different functions such that, for example, in humans, the 35,000 genes in the genome can give rise to more than 150,000 proteins. Thus, AS modulates gene function and expression and increases the number of proteins in higher eukaryotes. This flexibility allows the cells in an organism to fine-tune and subtly regulate cell activity. AS is not a random process but is highly regulated through the interaction of a large number of proteins called splicing factors with sequence signals in the pre-mRNA. Thus, in a particular cell type, the profile of splicing factors will determine the pattern of alternatively spliced transcripts of all of the genes being expressed. This will differ in different cell types, at different stages of development and in response to stimuli and, for example, stress conditions. To understand the regulation of gene expression at the level of alternative splicing, it is necessary to be able to measure changes in alternative splicing of multiple genes under different conditions. Over the last five years, estimates of the number of plant genes which undergo alternative splicing have risen from 7 to 35%. Despite at least a third of plant genes being alternatively spliced, little is known about how alternative splicing is regulated in plants. In particular, there is a need to better assess AS and its consequences, to address the co-ordinated regulation of AS in genes involved in the same biological process and to be able to examine cell- and tissue-specific alternative splicing. One of the major drawbacks currently is the lack of an accurate and reproducible system capable of monitoring multiple (10s to 100s) of AS events simultaneously. Research in animal systems has shown that alternative splicing is an essential aspect of gene expression with networks of alternative splicing regulation being superimposed on networks of transcriptional regulation. In plant systems, measuring global transcript levels is carried out routinely (transcriptomics) but alternative splicing and, in particular, the concept of co-ordinated and regulated alternative splicing has been largely ignored. We wish to establish a tool to monitor changes in alternative splicing of multiple plant genes in development and stress responses. The project will build collaborations between groups involved in aspects of developmental and stress biology of plants and the RNA biology/alternative splicing lab at the University of Dundee. The outcome of the project will be the demonstration that comprehensive process-specific AS RT-PCR panels can be used to accurately analyse changes in alternative splicing during development, under different conditions and in different mutant lines. By correlating patterns of changes in alternative splicing of specific genes or subsets of genes, information on the co-ordinated regulation of AS will be produced for the first time. Such information will be an integral part of systems approaches aimed at understanding interaction networks which regulate biological processes. The tool which we will develop will be of interest to plant scientists around the world. Although we will establish the tool by studying developmental processes and stress-induced genes in Arabidopsis, the system is very flexible and can be applied to examine any biological process in any plant species for which reasonable EST data exists.

Stem cells drive the regeneration and repair of damaged tissues and are, thus, essential for survival. The proliferative capacity of stem cells is, however, a double-edged sword. With every cell division there is a chance of an error occurring during DNA replication and/or repair, which makes stem cells prone to undergo malignant transformation into cancer cells. Fortunately, the body has protection barriers, known as tumour suppressor systems, that prevent uncontrolled growth of damaged cells. The most important of such systems is the p53 pathway. The p53 protein acts as a subcellular sensor that is triggered by potentially cancer-inducing stimuli, such as exposure to DNA damaging agents. In response to such stress conditions, p53 enhances DNA repair, inhibits cell proliferation, or induces programmed cell death. Due to these activities, p53 is regarded as highly attractive target for cancer therapy. Although the nearly 40,000 research articles published on p53 have revealed some of its secrets, they have also uncovered new layers of complexity, resulting in even more unanswered questions. Given the intrinsic complexity and implicit quantitative nature of some these questions, we aim to exploit theoretical thinking and mathematical modelling to gain deeper insight into the regulatory mechanisms of the p53 pathway. It is anticipated that the proposed research will complement and reinforce the biological knowledge acquired by empirical methods.