Novel Molecular Mechanisms of Membrane Traffic in Yeast

Proper membrane traffic is important to target cargo proteins to their designated locations in the cell and maintain homeostasis. Cargo protein traffic through the endomembrane system is a highly regulated process that depends, in part, on clathrin-coated vesicles. Clathrin-coated vesicles are used by the cell in endocytosis and post-Golgi traffic. Clathrin coat formation depends on the action of many proteins that help in the formation of clathrin vesicles. Some of these proteins include clathrin adaptors, proteins that select cargo to be packaged, vesicle terminating proteins, and other proteins that regulate each step of vesicle formation. This thesis addresses two related topics. The first topic explores the role of membrane trafficking proteins in cell survival in stress conditions, such as nutrient starvation. To survive nutrient starvation, cells can use a process known as autophagy. Autophagy is a mechanism to recycle cellular components to their molecular components. Although it was thought to contribute to survival during glucose starvation, our investigation indicates that autophagy is not essential for survival in glucose starvation for the budding yeast, Saccharomyces cerevisiae. Instead, we found that during glucose starvation the clearance of cell surface proteins and their traffic to, and degradation at, the vacuole (the lysosome in yeast) promotes cell survival. Furthermore, we found that autophagy is inhibited in glucose starved cells. These results suggest that endocytosis and endosomal traffic, not autophagy, is the mechanism used by the cell to survive in glucose starvation. The second topic covered by this thesis is the characterization of Art1/Ldb19, a member of the α-arrestins family. This topic started with the investigation of the clearance of cell surface proteins in glucose starved cells. This response was similar to the clearance of cell surface proteins caused by heat shock and cycloheximide treatment. These cell surface clearance events depend on the function of α-arrestins, a family of proteins involved in the ubiquitination of cargo proteins. Based on this similarity, we initiated an investigation of α-arrestins in glucose starvation-induced endocytosis. We found that the α-arrestin Art1/Ldb19 was required for efficient clearance of cell surface proteins in glucose starvation. Interestingly, Art1 localizes to internal structures that resemble trans-Golgi network (TGN) localization of clathrin adaptors at steady-state conditions. This localization could suggest an additional role for Art1, a known endocytic protein, in TGN traffic. The second part of this thesis explores the role of Art1 at the TGN. Using fluorescence microscopy approaches, we found that Art1 localizes to the late TGN and could potentially interact with the clathrin adaptor, AP-1. Additionally, we found genetic interactions of ART1 with another clathrin adaptor, GGA2, and a hypomorphic allele of clathrin. Finally, we found that deletion of ART1 suppresses secretion defects observed in cells that express a hypomorphic allele of clathrin. In summary, the doctoral research presented here provides novel mechanisms of membrane trafficking, with particular relevance for α-arrestins-dependent TGN traffic. Specifically, we found a novel mechanism for cell survival during glucose starvation independent of autophagy. Additionally, our data supports emerging evidence that suggest a role for Art1 at the TGN, in addition to its established role in endocytosis.PHDCell and Developmental BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/145944/1/majorge_1.pd

1883-06-14

The Old Commonwealth was a weekly newspaper published in Harrisonburg, Va., between 1865 and 1884

On environment difficulty and discriminating power

The final publication is available at Springer via http://dx.doi.org/10.1007/s10458-014-9257-1This paper presents a way to estimate the difficulty and discriminating power of any task instance. We focus on a very general setting for tasks: interactive (possibly multiagent) environments where an agent acts upon observations and rewards. Instead of analysing the complexity of the environment, the state space or the actions that are performed by the agent, we analyse the performance of a population of agent policies against the task, leading to a distribution that is examined in terms of policy complexity. This distribution is then sliced by the algorithmic complexity of the policy and analysed through several diagrams and indicators. The notion of environment response curve is also introduced, by inverting the performance results into an ability scale. We apply all these concepts, diagrams and indicators to two illustrative problems: a class of agent-populated elementary cellular automata, showing how the difficulty and discriminating power may vary for several environments, and a multiagent system, where agents can become predators or preys, and may need to coordinate. Finally, we discuss how these tools can be applied to characterise (interactive) tasks and (multi-agent) environments. These characterisations can then be used to get more insight about agent performance and to facilitate the development of adaptive tests for the evaluation of agent abilities.I thank the reviewers for their comments, especially those aiming at a clearer connection with the field of multi-agent systems and the suggestion of better approximations for the calculation of the response curves. The implementation of the elementary cellular automata used in the environments is based on the library 'CellularAutomaton' by John Hughes for R [58]. I am grateful to Fernando Soler-Toscano for letting me know about their work [65] on the complexity of 2D objects generated by elementary cellular automata. I would also like to thank David L. Dowe for his comments on a previous version of this paper. This work was supported by the MEC/MINECO projects CONSOLIDER-INGENIO CSD2007-00022 and TIN 2010-21062-C02-02, GVA project PROMETEO/2008/051, the COST - European Cooperation in the field of Scientific and Technical Research IC0801 AT, and the REFRAME project, granted by the European Coordinated Research on Long-term Challenges in Information and Communication Sciences & Technologies ERA-Net (CHIST-ERA), and funded by the Ministerio de Economia y Competitividad in Spain (PCIN-2013-037).José Hernández-Orallo (2015). On environment difficulty and discriminating power. Autonomous Agents and Multi-Agent Systems. 29(3):402-454. https://doi.org/10.1007/s10458-014-9257-1S402454293Anderson, J., Baltes, J., & Cheng, C. T. (2011). 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Christopher Stewart WALLACE (1933–2004) memorial special issue.Dowe, D. L., & Hernández-Orallo, J. (2012). IQ tests are not for machines, yet. Intelligence, 40(2), 77–81.Du, D. Z., & Ko, K. I. (2011). Theory of computational complexity (Vol. 58). London: Wiley-Interscience.Elo, A. E. (1978). The rating of chessplayers, past and present (Vol. 3). London: Batsford.Embretson, S. E., & Reise, S. P. (2000). Item response theory for psychologists. London: Lawrence Erlbaum.Fatès, N. & Chevrier, V. (2010). How important are updating schemes in multi-agent systems? an illustration on a multi-turmite model. In Proceedings of the 9th International Conference on Autonomous Agents and Multiagent Systems: volume 1-Volume 1 (pp. 533–540). International Foundation for Autonomous Agents and Multiagent Systems.Ferber, J. & Müller, J. P. (1996). Influences and reaction: A model of situated multiagent systems. In Proceedings of Second International Conference on Multi-Agent Systems (ICMAS-96) (pp. 72–79).Ferrando, P. J. (2009). Difficulty, discrimination, and information indices in the linear factor analysis model for continuous item responses. Applied Psychological Measurement, 33(1), 9–24.Ferrando, P. J. (2012). Assessing the discriminating power of item and test scores in the linear factor-analysis model. Psicológica, 33, 111–139.Gent, I. P., & Walsh, T. (1994). Easy problems are sometimes hard. Artificial Intelligence, 70(1), 335–345.Gershenson, C. & Fernandez, N. (2012). Complexity and information: Measuring emergence, self-organization, and homeostasis at multiple scales. Complexity, 18(2), 29–44.Gruner, S. (2010). Mobile agent systems and cellular automata. Autonomous Agents and Multi-agent Systems, 20(2), 198–233.Hardman, D. K., & Payne, S. J. (1995). Problem difficulty and response format in syllogistic reasoning. The Quarterly Journal of Experimental Psychology, 48(4), 945–975.He, J., Reeves, C., Witt, C., & Yao, X. (2007). A note on problem difficulty measures in black-box optimization: Classification, realizations and predictability. Evolutionary Computation, 15(4), 435–443.Hernández-Orallo, J. (2000). Beyond the turing test. Journal of Logic Language & Information, 9(4), 447–466.Hernández-Orallo, J. (2000). On the computational measurement of intelligence factors. In A. Meystel (Ed.), Performance metrics for intelligent systems workshop (pp. 1–8). Gaithersburg, MD: National Institute of Standards and Technology.Hernández-Orallo, J. (2000). Thesis: Computational measures of information gain and reinforcement in inference processes. AI Communications, 13(1), 49–50.Hernández-Orallo, J. (2010). A (hopefully) non-biased universal environment class for measuring intelligence of biological and artificial systems. In M. Hutter et al. (Ed.), 3rd International Conference on Artificial General Intelligence (pp. 182–183). Atlantis Press Extended report at http://users.dsic.upv.es/proy/anynt/unbiased.pdf .Hernández-Orallo, J., & Dowe, D. L. (2010). Measuring universal intelligence: Towards an anytime intelligence test. Artificial Intelligence, 174(18), 1508–1539.Hernández-Orallo, J., Dowe, D. L., España-Cubillo, S., Hernández-Lloreda, M. V., & Insa-Cabrera, J. (2011). On more realistic environment distributions for defining, evaluating and developing intelligence. In J. Schmidhuber, K. R. Thórisson, & M. Looks (Eds.), LNAI series on artificial general intelligence 2011 (Vol. 6830, pp. 82–91). Berlin: Springer.Hernández-Orallo, J., Dowe, D. L., & Hernández-Lloreda, M. V. (2014). Universal psychometrics: Measuring cognitive abilities in the machine kingdom. Cognitive Systems Research, 27, 50–74.Hernández-Orallo, J., Insa, J., Dowe, D. L. & Hibbard, B. (2012). Turing tests with turing machines. In A. Voronkov (Ed.), The Alan Turing Centenary Conference, Turing-100, Manchester, 2012, volume 10 of EPiC Series (pp. 140–156).Hernández-Orallo, J. & Minaya-Collado, N. (1998). A formal definition of intelligence based on an intensional variant of Kolmogorov complexity. In Proceedings of International Symposium of Engineering of Intelligent Systems (EIS’98) (pp. 146–163). ICSC Press.Hibbard, B. (2009). Bias and no free lunch in formal measures of intelligence. Journal of Artificial General Intelligence, 1(1), 54–61.Hoos, H. H. (1999). Sat-encodings, search space structure, and local search performance. In 1999 International Joint Conference on Artificial Intelligence (Vol. 16, pp. 296–303).Insa-Cabrera, J., Benacloch-Ayuso, J. L., & Hernández-Orallo, J. (2012). On measuring social intelligence: Experiments on competition and cooperation. In J. Bach, B. Goertzel, & M. Iklé (Eds.), AGI, volume 7716 of lecture notes in computer science (pp. 126–135). 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Champaign, IL: Wolfram Media.Zatuchna, Z., & Bagnall, A. (2009). Learning mazes with aliasing states: An LCS algorithm with associative perception. Adaptive Behavior, 17(1), 28–57.Zenil, H. (2010). Compression-based investigation of the dynamical properties of cellular automata and other systems. Complex Systems, 19(1), 1–28.Zenil, H. (2011). Une approche expérimentale à la théorie algorithmique de la complexité. PhD thesis, Dissertation in fulfilment of the degree of Doctor in Computer Science, Université de Lille.Zenil, H., Soler-Toscano, F., Delahaye, J. P. & Gauvrit, N. (2012). Two-dimensional kolmogorov complexity and validation of the coding theorem method by compressibility. arXiv, preprint arXiv:1212.6745

Robotic workcell analysis and object level programming

For many years robots have been programmed at manipulator or joint level without any real thought to the implementation of sensing until errors occur during program execution. For the control of complex, or multiple robot workcells, programming must be carried out at a higher level, taking into account the possibility of error occurrence. This requires the integration of decision information based on sensory data.Aspects of robotic workcell control are explored during this work with the object of integrating the results of sensor outputs to facilitate error recovery for the purposes of achieving completely autonomous operation.Network theory is used for the development of analysis techniques based on stochastic data. Object level programming is implemented using Markov chain theory to provide fully sensor integrated robot workcell control

From pathway to regulon in Arabidopsis

Combined bioinformatic approaches, using genomic and transcriptomic data, are applied to investigate the fatty acid biosynthesis pathway, at the molecular level, and in the context of the system biology of Arabidopsis. Fatty acids are essential components of all known bacterial and eukaryotic cells with critical role in cells as energy reserves and the metabolic precursors for biological membranes. The pathway for fatty acid synthesis seems to be conserved across all living systems. Acetyl-CoA carboxylase, a member of a superfamily of biotin-dependent enzymes, catalyzes the first committed step of the fatty acid biosynthesis pathway. Phylogenetic study exposed complex and intertwined evolutionary histories of this family, with multiple domain fusions and rearrangements. As revealed by meta-analysis of a wide array of Arabidopsis transcriptomic data, fatty acid biosynthesis is transcriptionally regulated, and this regulation not only extends across all pathway reactions, but also some substrate- and cofactor-producing reactions, thus defining a major transcriptionally co-regulated pathway. Meta-analysis of the transcriptome is extended to find groups of coexpressed genes (also called modules, or regulons) in the Arabidopsis genome. Major functionally-coherent gene groups were identified. These comprise development, information processing, defense, and metabolism, as well as tissue- and organelle-specific processes

April 7, 1997

The Breeze is the student newspaper of James Madison University in Harrisonburg, Virginia

Managing Expectations: the European Union and Human Security at the United Nations

This thesis explores the conditions under which the EU is an effective actor at the United Nations in the policy area of human security. Since the late 1990s, the United Nations has been increasingly active in addressing challenges posed by human security concerns. The concept of human security was introduced to emphasize the post-Cold War shift from a state-centred approach to security to an approach focused on the security of individuals. The EU is considered by some as a driving force in the UN policy process and has presented itself as a leader in the promotion of concrete initiatives to address human security challenges. This thesis seeks to examine whether the EU is truly an effective actor at the UN in human security negotiations and aims to identify conditions which influence the EU’s effectiveness. This thesis suggests that the analysis of conditions affecting the EU’s effectiveness at the UN requires the understanding of the ways in which a complex web of actors and institutions interact at three different levels: international, European Union and domestic. Using a multilevel game approach, this thesis examines the willingness of EU actors to work collectively at the UN (internal effectiveness) and the achievements of the EU’s objectives (external effectiveness). This thesis analyzes three cases of human security negotiations: 1) the ban on anti-personnel landmines, 2) the illicit trade in small arms and light weapons (SALW) and 3) the involvement of children in armed conflicts. Factors which have affected the EU’s internal and external effectiveness are identified in each of the case studies. The thesis uses qualitative methods such as expert interviews, documentary analysis and nonparticipant observation. This thesis demonstrates that, at the international level, the commitment of the EU to multilateralism can have an effect on the EU’s effectiveness in human security negotiations. The position of other key UN actors (such as the United States and the G-77) regarding a potential agreement also appears to directly influence EU Member States in achieving their objectives. The thesis argues that the use of consensus in the negotiations process can have a significant impact on the EU’s effectiveness. At the EU level, the analysis reveals that several key EU Member States channelled their efforts to convince their EU partners to act on all three issues. This thesis shows how the role of the EU presidency in coordinating the position of EU Member States can also affect the EU effectiveness in human security negotiations. The support of France, Germany and the United Kingdom, three dominant players in the EU’s Common Foreign and Security Policy, seems also particularly influential in negotiations. Finally, the case studies suggest that domestic politics can directly shape the EU’s effectiveness. Internal negotiations in EU Member States and the involvement of NGOs at the domestic level are two other factors which influence the EU’s effectiveness