Proceedings of the 11th Workshop on Nonmonotonic Reasoning

These are the proceedings of the 11th Nonmonotonic Reasoning Workshop. The aim of this series is to bring together active researchers in the broad area of nonmonotonic reasoning, including belief revision, reasoning about actions, planning, logic programming, argumentation, causality, probabilistic and possibilistic approaches to KR, and other related topics. As part of the program of the 11th workshop, we have assessed the status of the field and discussed issues such as: Significant recent achievements in the theory and automation of NMR; Critical short and long term goals for NMR; Emerging new research directions in NMR; Practical applications of NMR; Significance of NMR to knowledge representation and AI in general

Phylogenomic and structure-function relationship studies of proteins involved in EBV associated oncogenesis

This study covers the investigation of evolutionary and structure-function relationship aspects of several cancer related proteins. One part of the study deals with the investigation of a critical protein of Epstein-Barr Virus (EBV) the Nuclear Antigen 1 (EBNA1), and its interactions with different host proteins. One of these host proteins is a member of a large gene family, encoding ubiquitin specific proteases (USP), known as USP7. The second section of the thesis deals with the molecular evolution of the USP gene family. Another set of cellular proteins deregulated during EBV associated oncogenesis are members of the glycoside hydrolase (GH18) family. Their phylogenetic relationships and protein structures were investigated in the third section of this thesis. EBNA1 is the only EBV protein that consistently expressed in all latent forms of the EBV infections. The protein is involved in the genome maintenance and a substantial body of evidence suggests that it has a role in EBV associated oncogenesis. In this study, full length molecular models of the EBNA1 protein were generated using the programmes, I-TASSER, MOE and Modeller. The best models were selected on the basis of plausibility in structural and thermodynamical parameters and from this models of EBNA1 homologues of primates lymphocryptoviruses (LCVs) were generated. The C-terminal DNA binding and homodimerisation domain was predicted to be structurally similar between different LCV EBNA1 homologues, indicative of functional conservation. The central glycine alanine repeat (GAr) domain was predicted to be primarily composed of α helices, while almost all of the protein interaction region was found to be unstructured, irrespective of the prediction approach used and sequence origin. Predicted USP7 and Casein kinase 2 (CK2) binding sites and GAr were observed in the EBNA1 homologues of Old World primate LCVs, but not in the marmoset homologue suggesting the co-evolution of both these sites. Dimer conformations of the EBNA1 monomer models were constructed using SymmDock, where the C-terminal tail was predicted to wrap around the proline rich loop of another monomer, possibly contributing to dimer stability. This feature could be exploited in therapeutic design, hence an inhibitor peptide was designed and a preliminary evaluation was conducted to explore its ability to inhibit EBNA1 function in cell survival. The peptide array libraries of EBNA1 were used to investigate the binding regions and critical contact points between EBNA1 and partner proteins. Human EBP2 and USP7 proteins were expressed in bacteria and probed on the EBNA1 array. The data confirm the previously known binding region for EBNA1-EBP2 and EBNA1-USP7 interactions. In addition further information was gained regarding the critical contact residues and the potential role of phosphorylation of serine residues of EBNA1 in its binding with EBP2 and USP7. The human genome encodes nearly 100 USPs which contribute to regulate the turnover of cellular proteins. These homologues are divided into 16 paralogous groups, all sharing a characteristic peptidase C19 domain. Evolutionary relationships between these homologues were explored by datamining and the phylogenetic reconstruction of peptidase C19 domain sequences. The data reveal an ancient relationship between the genes, with expansion occurring throughout the course of evolution, but particularly at the base of the vertebrates, at the time of the two whole genome duplications. A comparison between the phylogenetic architecture and protein interaction networks suggests the parallel emergence of many molecular pathways and the associated USPs. The GH18 gene family includes chitinases and related non catalytic proteins. Most mammals encode at least three chitinases (CHIT1, CHIA/AMCase and CTBS), as well as several homologues encoding catalytically inactive chitinase-like proteins or chilectins. Phylogenomic analysis shows that the family has undergone extensive expansion, initiating with a duplication event at the root of the vertebrate tree, resulting in the origin of the ancestors of CHIT1 and CHIA. Two further duplications of ancestral CHIA predate the divergence of bony fishes, one leading to a newly identified paralogous group (we have termed CHIO). In tetrapods, additional CHIA duplications predate and postdate the amphibian/mammalian split and relics of some exist as pseudogenes in the human genome. Homology modelling of structurally unresolved GH18 homologues in mouse and human was conducted using Modeller and I-TASSER. All resolved and predicted structures share a TIM barrel (β/α)8 and α+β domain. A central ligand binding cavity was also found in all GH18 homologues. The variation in size and shape of different paralogous proteins, indicate the difference in their ligands specificity and in turn potential functions

Protein factors involved in the biogenesis of the mitochondrial ribosome

The mammalian mitochondria contain their own genome which encodes thirteen polypeptide components of the oxidative phosphorylation (OxPhos) system, and the mitochondrial (mt-) rRNAs and tRNAs required for their translation. The maturation of the mitochondrial ribosome requires both mt-rRNAs to undergo post-transcriptional chemical modifications, folding of the rRNA and assembly of the protein components assisted by numerous biogenesis factors. The post-transcriptional modifications of the mt-rRNAs include base methylations, 2’-O-ribose methylations and pseudouridylation. However, the exact function of these modifications is unknown. Many mitoribosome biogenesis factors still remain to be identified and characterised. This work aims to broaden our understanding of two proteins involved in mitoribosome biogenesis through the study of the function of an rRNA methyltransferase and a novel biogenesis factor. Firstly, we characterised MRM1 (mitochondrial rRNA methyltransferase 1), a highly conserved 2’-O-ribose methyltransferase. We confirmed that MRM1 modifies a guanine in the peptidyl (P) transferase region of the 16S mt-rRNA that specifically interacts with the 3’ end of the tRNA at the ribosomal P-site. In bacteria, the modification is dispensable for ribosomal biogenesis and cell viability under standard conditions. However, in yeast mitochondria, Mrm1p is vital for ribosomal assembly and function. We generated knockout cells lines using programmable nuclease technology, and characterised the possible effects of MRM1 depletion on mitochondrial translation and mitoribosome biogenesis. We demonstrated that neither the enzyme nor the modification is required for human mitoribosomal assembly and translation in our experimental setup. Secondly, we identified a novel mitochondrially-targeted putative RNA endonuclease, YbeY. Using YbeY knockout cell lines, we showed that depletion of YbeY leads to loss of cell viability and OxPhos function as a consequence of a severe decrease in mitochondrial translation. Northern blotting and transcriptomic analysis using next generation RNA-Seq revealed transcript-specific changes to steady state levels. This analysis identified mt-tRNASer as a potential target of YbeY. We investigated the effect of YbeY deficiency on mitoribosomal assembly by quantitative sucrose gradient fractionation and mass spectrometry. This analysis showed that the mt-SSU is depleted in YbeY knockout cells. Further, immunoaffinity purification identified MRPS11 as a key interactor of YbeY. We propose that YbeY is a multifunctional protein that performs endonucleolytic functions in the mitochondria and also acts as a mitochondrial ribosome biogenesis factor, assisting small subunit assembly through its interaction with MRPS11.Medical Research Counci

Bioinformatics

This book is divided into different research areas relevant in Bioinformatics such as biological networks, next generation sequencing, high performance computing, molecular modeling, structural bioinformatics, molecular modeling and intelligent data analysis. Each book section introduces the basic concepts and then explains its application to problems of great relevance, so both novice and expert readers can benefit from the information and research works presented here

Emergent Design

Explorations in Systems Phenomenology in Relation to Ontology, Hermeneutics and the Meta-dialectics of Design SYNOPSIS A Phenomenological Analysis of Emergent Design is performed based on the foundations of General Schemas Theory. The concept of Sign Engineering is explored in terms of Hermeneutics, Dialectics, and Ontology in order to define Emergent Systems and Metasystems Engineering based on the concept of Meta-dialectics. ABSTRACT Phenomenology, Ontology, Hermeneutics, and Dialectics will dominate our inquiry into the nature of the Emergent Design of the System and its inverse dual, the Meta-system. This is an speculative dissertation that attempts to produce a philosophical, mathematical, and theoretical view of the nature of Systems Engineering Design. Emergent System Design, i.e., the design of yet unheard of and/or hitherto non-existent Systems and Metasystems is the focus. This study is a frontal assault on the hard problem of explaining how Engineering produces new things, rather than a repetition or reordering of concepts that already exist. In this work the philosophies of E. Husserl, A. Gurwitsch, M. Heidegger, J. Derrida, G. Deleuze, A. Badiou, G. Hegel, I. Kant and other Continental Philosophers are brought to bear on different aspects of how new technological systems come into existence through the midwifery of Systems Engineering. Sign Engineering is singled out as the most important aspect of Systems Engineering. We will build on the work of Pieter Wisse and extend his theory of Sign Engineering to define Meta-dialectics in the form of Quadralectics and then Pentalectics. Along the way the various ontological levels of Being are explored in conjunction with the discovery that the Quadralectic is related to the possibility of design primarily at the Third Meta-level of Being, called Hyper Being. Design Process is dependent upon the emergent possibilities that appear in Hyper Being. Hyper Being, termed by Heidegger as Being (Being crossed-out) and termed by Derrida as Differance, also appears as the widest space within the Design Field at the third meta-level of Being and therefore provides the most leverage that is needed to produce emergent effects. Hyper Being is where possibilities appear within our worldview. Possibility is necessary for emergent events to occur. Hyper Being possibilities are extended by Wild Being propensities to allow the embodiment of new things. We discuss how this philosophical background relates to meta-methods such as the Gurevich Abstract State Machine and the Wisse Metapattern methods, as well as real-time architectural design methods as described in the Integral Software Engineering Methodology. One aim of this research is to find the foundation for extending the ISEM methodology to become a general purpose Systems Design Methodology. Our purpose is also to bring these philosophical considerations into the practical realm by examining P. Bourdieu’s ideas on the relationship between theoretical and practical reason and M. de Certeau’s ideas on practice. The relationship between design and implementation is seen in terms of the Set/Mass conceptual opposition. General Schemas Theory is used as a way of critiquing the dependence of Set based mathematics as a basis for Design. The dissertation delineates a new foundation for Systems Engineering as Emergent Engineering based on General Schemas Theory, and provides an advanced theory of Design based on the understanding of the meta-levels of Being, particularly focusing upon the relationship between Hyper Being and Wild Being in the context of Pure and Process Being

In/sight: The art of creating self-reflexive spaces. An investigation of transdisciplinary practitioner/practice

At a time when, arguably more than ever before in human history, the human mind needs to become more adaptive, and adapting, to meet the increasingly complex, ambiguous, uncertain conditions of the world in which we live, any practices that can effect lasting expansion of our ways of seeing, thinking and acting in relation to self, others, and the world may be considered a useful and valuable contribution to human knowledge and practices. This practice-led research conducted over a span of eight years demonstrates the capacity of an arts-based system of knowing and knowledge production to give rise to just such effects. Creative contemplation® is a methodology of material meditation originated and evolved within an experimental, transdisciplinary, commercial design practice - a methodology that proves able to generate self-reflexive spaces for myself, and for others who are neither trained nor practised in creative arts, and it is able to do so within the context of everyday practices. This bricolage system of knowing and knowledge production primarily derives from the arts but also variously derives from Australian Indigenous cultural practices as well as psychology, somatic therapy, Western and Eastern philosophy, and traditions of meditation - most particularly Japanese forms of Zen. As such, the transdisciplinary nature of Creative contemplation® accesses and activates a continuum of somatic and intellectual ways of knowing that at once both transcend and extend habitual ontological and epistemological frameworks. This investigation draws on the experience and knowledge gained in a highly successful, five year collaboration with a courageous organisation that risks engaging me to create and conduct extensive learning fora in which Creative contemplation® is used to increase individual and collective capacity of environmental scientists, and other staff, grappling with the complex matter of sustainability, and the uncertain future of the natural environment and humanity’s prospect inextricably interwoven within it. In situating my work in relation to the orthodoxy of investigating and cultivating mind in the area of business known as organisational learning and development, and in relation to the emerging field of arts in business, its significant contribution to knowledge and practices in this arena come clearly into view, but, by its very nature, such transdisciplinary practice-research transcends boundaries of any single field allowing contributions to knowledge and practices to be far more broadly inferred. Through studio inquiry, and practice-led and literature-based research the philosophical, theoretical, methodological and practical frameworks are created that support, and make explicit, the ontology and operations of Creative contemplation® methodology, the learning fora with others that I conceive as a species of performative installation, and my agency and role as practitioner within these fora that I cast as being (an) Attendant - a specialised model and mode of facilitation commensurate with the potency of arts-based knowing to investigate and cultivate workings of mind and heart

Baskets of offerings: Design, nature, animism, and pedagogy

This dissertation explores how an animist spirituality redirects design. Design has long been understood as the professional practice of creating artefacts, systems, and communications for modern Western “civilization.” Recently, many scholars have been calling for a redirection of design’s talents and agency towards holistic, ecological and ethical practices. To do this, I argue, designers need to build an understanding and a connection with nature, ecological literacy, a visceral understanding of the Earth, and a spiritual knowing that we are interconnected and inseparable from all beings. I learned much of this during my childhood experiences on a farm, and during my exploration of contemplative practices. Through my journaling and my studies, I found that the spiritual and personal were artificially separated from the professional disciplines. I reunited important parts of myself that had been fragmented or split off during my professional teaching and professional design career. Buddhist mindfulness and meditation practices offer psychophysical learning. Contrary to academic intellectual traditions, these offer a path to understanding animist spirituality within mind, body, and heart. I search for pathways to extend this deep learning through somatic and experiential pedagogies in design. I relate several stories of how my colleagues and I have integrated animist, intersubjective, and contemplative practices into design pedagogy. I look for practices to support the embodied, relational, and experiential forms of exploration that can open opportunities for animist ways of knowing. We become aware, with carnal vitality, of our physical and emotional selves in the process. We come to understand ourselves and our bodies as fully implicated in seeing, reflecting, understanding, and practicing design. Reflections, stories, essays, and journal extracts are sorted into a series of baskets rather than the traditional thesis form of chapters. Meditative practices interweave throughout. This collection of possibilities allows a métissage of ideas rather than a scripted or definitive study