The development of a rich multimedia training environment for crisis management: using emotional affect to enhance learning

PANDORA is an EU FP7-funded project developing a novel training and learning environment for Gold Commanders, individuals who carry executive responsibility for the services and facilities identified as strategically critical e.g. Police, Fire, in crisis management strategic planning situations. A key part of the work for this project is considering the emotional and behavioural state of the trainees, and the creation of more realistic, and thereby stressful, representations of multimedia information to impact on the decision-making of those trainees. Existing training models are predominantly paper-based, table-top exercises, which require an exercise of imagination on the part of the trainees to consider not only the various aspects of a crisis situation but also the impacts of interventions, and remediating actions in the event of the failure of an intervention. However, existing computing models and tools are focused on supporting tactical and operational activities in crisis management, not strategic. Therefore, the PANDORA system will provide a rich multimedia information environment, to provide trainees with the detailed information they require to develop strategic plans to deal with a crisis scenario, and will then provide information on the impacts of the implementation of those plans and provide the opportunity for the trainees to revise and remediate those plans. Since this activity is invariably multi-agency, the training environment must support group-based strategic planning activities and trainees will occupy specific roles within the crisis scenario. The system will also provide a range of non-playing characters (NPC) representing domain experts, high-level controllers (e.g. politicians, ministers), low-level controllers (tactical and operational commanders), and missing trainee roles, to ensure a fully populated scenario can be realised in each instantiation. Within the environment, the emotional and behavioural state of the trainees will be monitored, and interventions, in the form of environmental information controls and mechanisms impacting on the stress levels and decisionmaking capabilities of the trainees, will be used to personalise the training environment. This approach enables a richer and more realistic representation of the crisis scenario to be enacted, leading to better strategic plans and providing trainees with structured feedback on their performance under stress

LIDA: A Working Model of Cognition

In this paper we present the LIDA architecture as a working model of cognition. We argue that such working models are broad in scope and address real world problems in comparison to experimentally based models which focus on specific pieces of cognition. While experimentally based models are useful, we need a working model of cognition that integrates what we know from neuroscience, cognitive science and AI. The LIDA architecture provides such a working model. A LIDA based cognitive robot or software agent will be capable of multiple learning mechanisms. With artificial feelings and emotions as primary motivators and learning facilitators, such systems will ‘live’ through a developmental period during which they will learn in multiple ways to act in an effective, human-like manner in complex, dynamic, and unpredictable environments. We discuss the integration of the learning mechanisms into the existing IDA architecture as a working model of cognition

An efficient MPI/OpenMP parallelization of the Hartree-Fock method for the second generation of Intel Xeon Phi processor

Modern OpenMP threading techniques are used to convert the MPI-only Hartree-Fock code in the GAMESS program to a hybrid MPI/OpenMP algorithm. Two separate implementations that differ by the sharing or replication of key data structures among threads are considered, density and Fock matrices. All implementations are benchmarked on a super-computer of 3,000 Intel Xeon Phi processors. With 64 cores per processor, scaling numbers are reported on up to 192,000 cores. The hybrid MPI/OpenMP implementation reduces the memory footprint by approximately 200 times compared to the legacy code. The MPI/OpenMP code was shown to run up to six times faster than the original for a range of molecular system sizes.Comment: SC17 conference paper, 12 pages, 7 figure

Pharmacokinetics of the cyclosporine-ketoconazole interaction in dogs

Numerous clinical reports have documented an increase in trough blood concentrations of cyclosporine in transplant recipients treated concomitantly with ketoconazole. The objective of this study was to elucidate the mechanism(s) underlying the cyclosporine-ketoconazole interaction using a choledochoureterostomy dog model. Five male beagle dogs received a 4 mg/kg, i.v. bolus dose of cyclosporine either alone or on day seven of a 10-day, 13 mg/kg/day, oral dosing regimen of ketoconazole. Blood samples were collected prior to and at predetermined times for 60 hrs after the cyclosporine dose, while the bile/urine mixture was collected quantitatively for 96 hours after the cyclosporine dose. Ketoconazole decreased the systemic clearance of cyclosporine from 7.0 ml/min/kg to 2.5 ml/min/kg. The terminal disposition rate constant was also decreased significantly from 0.0794 to 0.0354 hrs-1. Ketoconazole caused no significant changes in cyclosporine steady state volume of distribution, or plasma unbound fraction. Ketoconazole did not significantly alter the excretion of cyclosporine and various cyclosporine metabolites in the bile/urine mixture. Inhibition of hepatic drug metabolizing enzymes appears to be the primary reason for the ketoconazole induced elevation in cyclosporine concentration

Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis

Accumulating data indicate that the ubiquitin-proteasome system controls apoptosis by regulating the level and the function of key regulatory proteins. In this study, we identified Trim17, a member of the TRIM/RBCC protein family, as one of the critical E3 ubiquitin ligases involved in the control of neuronal apoptosis upstream of mitochondria. We show that expression of Trim17 is increased both at the mRNA and protein level in several in vitro models of transcription-dependent neuronal apoptosis. Expression of Trim17 is controlled by the PI3K/Akt/GSK3 pathway in cerebellar granule neurons (CGN). Moreover, the Trim17 protein is expressed in vivo, in apoptotic neurons that naturally die during post-natal cerebellar development. Overexpression of active Trim17 in primary CGN was sufficient to induce the intrinsic pathway of apoptosis in survival conditions. This pro-apoptotic effect was abolished in Bax(-/-) neurons and depended on the E3 activity of Trim17 conferred by its RING domain. Furthermore, knock-down of endogenous Trim17 and overexpression of dominant-negative mutants of Trim17 blocked trophic factor withdrawal-induced apoptosis both in CGN and in sympathetic neurons. Collectively, our data are the first to assign a cellular function to Trim17 by showing that its E3 activity is both necessary and sufficient for the initiation of neuronal apoptosis. Cell Death and Differentiation (2010) 17, 1928-1941; doi: 10.1038/cdd.2010.73; published online 18 June 201

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Developmental differences in the effects of repeated interviews and interviewer bias on young children's event memory and false reports.

The present study investigated developmental differences in the effects of repeated interviews and interviewer bias on children’s memory and suggestibility. Three- and 5-year-olds were singly or repeatedly interviewed about a play event by a highly biased or control interviewer. Children interviewed once by the biased interviewer after a long delay made the most errors. Children interviewed repeatedly, regardless of interviewer bias, were more accurate and less likely to falsely claim that they played with a man. In free recall, among children questioned once after a long delay by the biased interviewer, 5-year-olds were more likely than were 3-year-olds to claim falsely that they played with a man. However, in response to direct questions, 3-year-olds were more easily manipulated into implying that they played with him. Findings suggest that interviewer bias is particularly problematic when children’s memory has weakened. In contrast, repeated interviews that occur a short time after a to-be-remembered event do not necessarily increase children’s errors, even when interviews include misleading questions and interviewer bias. Implications for developmental differences in memory and suggestibility are discussed

Genome-wide profiling of G protein-coupled receptors in cerebellar granule neurons using high-throughput, real-time PCR

<p>Abstract</p> <p>Background</p> <p>G protein-coupled receptors (GPCRs) are major players in cell communication, regulate a whole range of physiological functions during development and throughout adult life, are affected in numerous pathological situations, and constitute so far the largest class of drugable targets for human diseases. The corresponding genes are usually expressed at low levels, making accurate, genome-wide quantification of their expression levels a challenging task using microarrays.</p> <p>Results</p> <p>We first draw an inventory of all endo-GPCRs encoded in the murine genome. To profile GPCRs genome-wide accurately, sensitively, comprehensively, and cost-effectively, we designed and validated a collection of primers that we used in quantitative RT-PCR experiments. We experimentally validated a statistical approach to analyze genome-wide, real-time PCR data. To illustrate the usefulness of this approach, we determined the repertoire of GPCRs expressed in cerebellar granule neurons and neuroblasts during postnatal development.</p> <p>Conclusions</p> <p>We identified tens of GPCRs that were not detected previously in this cell type; these GPCRs represent novel candidate players in the development and survival of cerebellar granule neurons. The sequences of primers used in this study are freely available to those interested in quantifying GPCR expression comprehensively.</p

Opposing Effects of Sirtuins on Neuronal Survival: SIRT1-Mediated Neuroprotection Is Independent of Its Deacetylase Activity

Background: Growing evidence suggests that sirtuins, a family of seven distinct NAD-dependent enzymes, are involved in the regulation of neuronal survival. Indeed, SIRT1 has been reported to protect against neuronal death, while SIRT2 promotes neurodegeneration. The effect of SIRTs 3–7 on the regulation of neuronal survival, if any, has yet to be reported. Methodology and Principal Findings: We examined the effect of expressing each of the seven SIRT proteins in healthy cerebellar granule neurons (CGNs) or in neurons induced to die by low potassium (LK) treatment. We report that SIRT1 protects neurons from LK-induced apoptosis, while SIRT2, SIRT3 and SIRT6 induce apoptosis in otherwise healthy neurons. SIRT5 is generally localized to both the nucleus and cytoplasm of CGNs and exerts a protective effect. In a subset of neurons, however, SIRT5 localizes to the mitochondria and in this case it promotes neuronal death. Interestingly, the protective effect of SIRT1 in neurons is not reduced by treatments with nicotinamide or sirtinol, two pharmacological inhibitors of SIRT1. Neuroprotection was also observed with two separate mutant forms of SIRT1, H363Y and H355A, both of which lack deacetylase activity. Furthermore, LK-induced neuronal death was not prevented by resveratrol, a pharmacological activator of SIRT1, at concentrations at which it activates SIRT1. We extended our analysis to HT-22 neuroblastoma cells which can be induced to die by homocysteic acid treatment. While the effects of most of the SIRT proteins were similar to that observed in CGNs, SIRT6 was modestly protective against homocysteic acid toxicity in HT-22 cells. SIRT5 was generally localized in th

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

Although the role of the microtubule-binding domain of the tau protein in the modulation of microtubule assembly is widely established, other possible functions of this protein have been poorly investigated. We have analyzed the effect of adenovirally mediated expression of two fragments of the N-terminal portion - free of microtubule-binding domain - of the tau protein in cerebellar granule neurons (CGNs). We found that while the expression of the tau (1-230) fragment, as well as of full-length tau, inhibits the onset of apoptosis, the tau (1-44) fragment exerts a powerful toxic action on the same neurons. The antiapoptotic action of tau (1-230) is exerted at the level of Akt-mediated activation of the caspase cascade. On the other hand, the toxic action of the (1-44) fragment is not prevented by inhibitors of CGN apoptosis, but is fully inhibited by NMDA receptor antagonists. These findings point to a novel, physiological role of the N-terminal domain of tau, but also underlay that its possible proteolytic truncation mediated by apoptotic proteases may generate a highly toxic fragment that could contribute to neuronal death