Endogenous Presentation of CD8+ T Cell Epitopes from Epstein-Barr Virus–encoded Nuclear Antigen 1

Epstein-Barr virus (EBV)–encoded nuclear antigen (EBNA)1 is thought to escape cytotoxic T lymphocyte (CTL) recognition through either self-inhibition of synthesis or by blockade of proteasomal degradation by the glycine-alanine repeat (GAr) domain. Here we show that EBNA1 has a remarkably varied cell type–dependent stability. However, these different degradation rates do not correspond to the level of major histocompatibility complex class I–restricted presentation of EBNA1 epitopes. In spite of the highly stable expression of EBNA1 in B cells, CTL epitopes derived from this protein are efficiently processed and presented to CD8+ T cells. Furthermore, we show that EBV-infected B cells can readily activate EBNA1-specific memory T cell responses from healthy virus carriers. Functional assays revealed that processing of these EBNA1 epitopes is proteasome and transporter associated with antigen processing dependent. We also show that the endogenous presentation of these epitopes is dependent on the newly synthesized protein rather than the long-lived stable EBNA1. Based on these observations, we propose that defective ribosomal products, not the full-length antigen, are the primary source of endogenously processed CD8+ T cell epitopes from EBNA1

Constraints on energetic particles in the Fleischmann-Pons experiment

In recent Fleischmann–Pons experiments carried out by different groups, a thermal signal is seen indicative of excess energy production of a magnitude much greater than can be accounted for by chemistry. Correlated with the excess heat appears to be 4He, with the associated energy near 24 MeV per helium atom. In nuclear reactions, the energy produced is expressed through the kinetic energy of the products; hence, it would be natural to assume that some of the reaction energy ends up as kinetic energy of the 4He nucleus. Depending on the energy that the helium nucleus is born with, it will result in radiation (such as neutrons or x-rays) that can be seen outside of the cell. We have computed estimates of the expected neutron and x-ray emission as a function of helium energy and compared the results with upper limits taken from experiments. Experimental results with upper limits of neutron emission between 0.008 and 0.8 n/J are found to correspond to upper limits in alpha energy between 6.2 and 20.2 keV

Memory consolidation in the cerebellar cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA(A) agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage

Evaluating how agent methodologies support the specification of the normative environment through the development process

[EN] Due to the increase in collaborative work and the decentralization of processes in many domains, there is an expanding demand for large-scale, flexible and adaptive software systems to support the interactions of people and institutions distributed in heterogeneous environments. Commonly, these software applications should follow specific regulations meaning the actors using them are bound by rights, duties and restrictions. Since this normative environment determines the final design of the software system, it should be considered as an important issue during the design of the system. Some agent-oriented software engineering methodologies deal with the development of normative systems (systems that have a normative environment) by integrating the analysis of the normative environment of a system in the development process. This paper analyses to what extent these methodologies support the analysis and formalisation of the normative environment and highlights some open issues of the topic.This work is partially supported by the PROMETEOII/2013/019, TIN2012-36586-C03-01, FP7-29493, TIN2011-27652-C03-00, CSD2007-00022 projects, and the CASES project within the 7th European Community Framework Program under the grant agreement No 294931.Garcia Marques, ME.; Miles, S.; Luck, M.; Giret Boggino, AS. (2014). Evaluating how agent methodologies support the specification of the normative environment through the development process. Autonomous Agents and Multi-Agent Systems. 1-20. https://doi.org/10.1007/s10458-014-9275-zS120Cossentino, M., Hilaire, V., Molesini, A., & Seidita, V. (Eds.). (2014). Handbook on agent-oriented design processes (Vol. VIII, 569 p. 508 illus.). Berlin: Springer.Akbari, O. (2010). A survey of agent-oriented software engineering paradigm: Towards its industrial acceptance. 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Verhagen (Eds.), Normative multi-agent systems, number 09121 in Dagstuhl seminar proceedings.Boella, G., Torre, L., & Verhagen, H. (2006). Introduction to normative multiagent systems. Computational and Mathematical Organization Theory, 12(2–3), 71–79.Bogdanovych, A., Esteva, M., Simoff, S., Sierra, C., & Berger, H. (2008). A methodology for developing multiagent systems as 3d electronic institutions. In M. Luck & L. Padgham (Eds.), Agent-Oriented Software Engineering VIII (Vol. 4951, pp. 103–117). Lecture Notes in Computer Science. Berlin: Springer.Boissier, O., Padget, J., Dignum, V., Lindemann, G., Matson, E., Ossowski, S., Sichman, J., & Vazquez-Salceda, J. (2006). Coordination, organizations, institutions and norms in multi-agent systems. LNCS (LNAI) (Vol. 3913).Bordini, R. H., Fisher, M., Visser, W., & Wooldridge, M. (2006). Verifying multi-agent programs by model checking. In Autonomous agents and multi-agent systems (Vol. 12, pp. 239–256). 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Lecture Notes in Computer Science (Vol. 3913, pp. 99–113). Springer. Berlin.Criado, N., Argente, E., Garrido, A., Gimeno, J. A., Igual, F., Botti, V., Noriega, P., & Giret, A. (2011). Norm enforceability in Electronic Institutions? In Coordination, organizations, institutions, and norms in agent systems VI (Vol. 6541, pp. 250–267). Springer.Dellarocas, C., & Klein, M. (2001). Contractual agent societies. In R. Conte & C. Dellarocas (Eds.), Social order in multiagent systems (Vol. 2, pp. 113–133)., Multiagent Systems, Artificial Societies, and Simulated Organizations New York: Springer.DeLoach, S. A. (2008). Developing a multiagent conference management system using the o-mase process framework. In Proceedings of the international conference on agent-oriented software engineering VIII (pp. 168–181).DeLoach, S. A., & Garcia-Ojeda, J. C. (2010). O-mase; a customisable approach to designing and building complex, adaptive multi-agent systems. International Journal of Agent-Oriented Software Engineering, 4(3), 244–280.DeLoach, S. A., Padgham, L., Perini, A., Susi, A., & Thangarajah, J. (2009). Using three aose toolkits to develop a sample design. International Journal Agent-Oriented Software Engineering, 3, 416–476.Dignum, F., Dignum, V., Thangarajah, J., Padgham, L., & Winikoff, M. (2007). Open agent systems? Eighth international workshop on agent oriented software engineering (AOSE) in AAMAS07.Dignum, V. (2003). A model for organizational interaction:based on agents, founded in logic. PhD thesis, Utrecht University.Dignum, V., Meyer, J., Dignum, F., & Weigand, H. (2003). Formal specification of interaction in agent societies. Formal approaches to agent-based systems (Vol. 2699).Dignum, V., Vazquez-Salceda, J., & Dignum, F. (2005). Omni: Introducing social structure, norms and ontologies into agent organizations. In R. Bordini, M. Dastani, J. Dix, & A. Seghrouchni (Eds.)Programming multi-agent systems. Lecture Notes in Computer Science (Vol. 3346, pp. 181–198). Berlin: Springer.d’Inverno, M., Luck, M., Noriega, P., Rodriguez-Aguilar, J., & Sierra, C. (2012). Communicating open systems, 186, 38–94.Elsenbroich, C., & Gilbert, N. (2014). Agent-based modelling. In Modelling norms (pp. 65–84). Dordrecht: Springer.Esteva, M., Rosell, B., Rodriguez, J. A., & Arcos, J. L. (2004). AMELI: An agent-based middleware for electronic institutions. In AAMAS04 (pp. 236–243).Fenech, S., Pace, G. J., & Schneider, G. (2009). Automatic conflict detection on contracts. In Proceedings of the 6th international colloquium on theoretical aspects of computing, ICTAC ’09 (pp. 200–214).Garbay, C., Badeig, F., & Caelen, J. (2012). Normative multi-agent approach to support collaborative work in distributed tangible environments. In Proceedings of the ACM 2012 conference on computer supported cooperative work companion, CSCW ’12 (pp. 83–86). New York, NY: ACM.Garcia, E., Giret, A., & Botti, V. (2011). Regulated open multi-agent systems based on contracts. In Information Systems Development (pp. 243–255).Garcia, E., Tyson, G., Miles, S., Luck, M., Taweel, A., Staa, T. V., & Delaney, B. (2012). An analysis of agent-oriented engineering of e-health systems. In 13th international eorkshop on sgent-oriented software engineering (AOSE-AAMAS).Garcia, E., Tyson, G., Miles, S., Luck, M., Taweel, A., Staa, T. V., and Delaney, B. (2013). Analysing the Suitability of Multiagent Methodologies for e-Health Systems. In Agent-Oriented Software Engineering XIII, volume 7852, pages 134–150. Springer-Verlag.Garrido, A., Giret, A., Botti, V., & Noriega, P. (2013). mWater, a case study for modeling virtual markets. In New perspectives on agreement technologies (Vol. Law, Gover, pp. 563–579). Springer.Gteau, B., Boissier, O., & Khadraoui, D. (2006). Multi-agent-based support for electronic contracting in virtual enterprises. IFAC Symposium on Information Control Problems in Manufacturing (INCOM), 150(3), 73–91.Hollander, C. D., & Wu, A. S. (2011). The current state of normative agent-based systems. Journal of Artificial Societies and Social Simulation, 14(2), 6.Hsieh, F.-S. (2005). Automated negotiation based on contract net and petri net. In E-commerce and web technologies. Lecture Notes in Computer Science (Vol. 3590, pp. 148–157).Kollingbaum, M., Jureta, I. J., Vasconcelos, W., & Sycara, K. (2008). Automated requirements-driven definition of norms for the regulation of behavior in multi-agent systems. In Proceedings of the AISB 2008 workshop on behaviour regulation in multi-agent systems, Aberdeen, Scotland, U.K., April 2008.Li, T., Balke, T., Vos, M., Satoh, K., & Padget, J. (2013). Detecting conflicts in legal systems. In Y. Motomura, A. Butler, & D. Bekki (Eds.), New Frontiers in Artificial Intelligence (Vol. 7856, pp. 174–189)., Lecture Notes in Computer Science Berlin Heidelberg: Springer.Lomuscio, A., Qu, H., & Solanki, M. (2010) Towards verifying contract regulated service composition. Journal of Autonomous Agents and Multi-Agent Systems (pp. 1–29).Lopez, F., Luck, M., & d’Inverno, M. (2006). A normative framework for agent-based systems. Computational and Mathematical Organization Theory, 12, 227–250.Lpez, F. y, Luck, M., & dInverno, M. (2006). A normative framework for agent-based systems. Computational and Mathematical Organization Theory, 12(2–3), 227–250.Mader, P., & Egyed, A. (2012). Assessing the effect of requirements traceability for software maintenance. In 28th IEEE International Conference on Software Maintenance (ICSM) (pp. 171–180), Sept 2012.Mao, X., & Yu, E. (2005). Organizational and social concepts in agent oriented software engineering. In AOSE IV. Lecture Notes in Artificial Intelligence (Vol. 3382, pp. 184–202).Meyer, J.-J. C., & Wieringa, R. J. (Eds.). (1993). Deontic logic in computer science: Normative system specification. Chichester, UK: Wiley.Okouya, D., & Dignum, V. (2008). Operetta: A prototype tool for the design, analysis and development of multi-agent organizations (demo paper). In AAMAS (pp. 1667–1678).Malone, T. W., Smith J. B., & Olson, G. M. (2001). Coordination theory and collaboration technology. Mahwah, NJ: Lawrence Erlbaum Associates.Oren, N., Panagiotidi, S., Vázquez-Salceda, J., Modgil, S., Luck, M., & Miles, S. (2009). Towards a formalisation of electronic contracting environments. COIN (pp. 156–171).Osman, N., Robertson, D., & Walton, C. (2006). Run-time model checking of interaction and deontic models for multi-agent systems. In AAMAS ’06: Proceedings of the fifth international joint conference on Autonomous agents and multiagent systems (pp. 238–240). 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Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

High platelet reactivity in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Randomised controlled trial comparing prasugrel and clopidogrel

Background: Prasugrel is more effective than clopidogrel in reducing platelet aggregation in acute coronary syndromes. Data available on prasugrel reloading in clopidogrel treated patients with high residual platelet reactivity (HRPR) i.e. poor responders, is limited. Objectives: To determine the effects of prasugrel loading on platelet function in patients on clopidogrel and high platelet reactivity undergoing percutaneous coronary intervention for acute coronary syndrome (ACS). Patients: Patients with ACS on clopidogrel who were scheduled for PCI found to have a platelet reactivity ≥40 AUC with the Multiplate Analyzer, i.e. “poor responders” were randomised to prasugrel (60 mg loading and 10 mg maintenance dose) or clopidogrel (600 mg reloading and 150 mg maintenance dose). The primary outcome measure was proportion of patients with platelet reactivity <40 AUC 4 hours after loading with study medication, and also at one hour (secondary outcome). 44 patients were enrolled and the study was terminated early as clopidogrel use decreased sharply due to introduction of newer P2Y12 inhibitors. Results: At 4 hours after study medication 100% of patients treated with prasugrel compared to 91% of those treated with clopidogrel had platelet reactivity <40 AUC (p = 0.49), while at 1 hour the proportions were 95% and 64% respectively (p = 0.02). Mean platelet reactivity at 4 and 1 hours after study medication in prasugrel and clopidogrel groups respectively were 12 versus 22 (p = 0.005) and 19 versus 34 (p = 0.01) respectively. Conclusions: Routine platelet function testing identifies patients with high residual platelet reactivity (“poor responders”) on clopidogrel. A strategy of prasugrel rather than clopidogrel reloading results in earlier and more sustained suppression of platelet reactivity. Future trials need to identify if this translates into clinical benefit

Heritage branding orientation: The case of Ach. Brito and the dynamics between corporate and product heritage brands

The notion of heritage branding orientation is introduced and explicated. Heritage branding orientation is designated as embracing both product and corporate brands and differs from corporate heritage brand orientation which has an explicit corporate focus. Empirical insights are drawn from an in-depth and longitudinal case study of Ach. Brito, a celebrated Portuguese manufacturer of soaps and toiletries. This study shows how, by the pursuance of a strategy derived from a heritage branding orientation Ach. Brito – after a prolonged period of decline – achieved a dramatic strategic turnaround. The findings reveal how institutional heritage can be a strategic resource via its adoption and activation at both the product and corporate levels. Moreover, the study showed how the bi-lateral interplay between product and corporate brand levels can be mutually reinforcing. In instrumental terms, the study shows how heritage can be activated and articulated in different ways. For instance, it can re-position both product and/or corporate brands; it can be meaningfully informed by product brand heritage and shape corporate heritage; and can be of strategic importance to both medium-sized and small enterprises

Improving clinical research and cancer care delivery in community settings: evaluating the NCI community cancer centers program

Abstract Background In this article, we describe the National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) pilot and the evaluation designed to assess its role, function, and relevance to the NCI's research mission. In doing so, we describe the evolution of and rationale for the NCCCP concept, participating sites' characteristics, its multi-faceted aims to enhance clinical research and quality of care in community settings, and the role of strategic partnerships, both within and outside of the NCCCP network, in achieving program objectives. Discussion The evaluation of the NCCCP is conceptualized as a mixed method multi-layered assessment of organizational innovation and performance which includes mapping the evolution of site development as a means of understanding the inter- and intra-organizational change in the pilot, and the application of specific evaluation metrics for assessing the implementation, operations, and performance of the NCCCP pilot. The assessment of the cost of the pilot as an additional means of informing the longer-term feasibility and sustainability of the program is also discussed. Summary The NCCCP is a major systems-level set of organizational innovations to enhance clinical research and care delivery in diverse communities across the United States. Assessment of the extent to which the program achieves its aims will depend on a full understanding of how individual, organizational, and environmental factors align (or fail to align) to achieve these improvements, and at what cost