HOX genes: seductive science, mysterious mechanisms

HOX genes are evolutionarily highly conserved. The HOX proteins which they encode are master regulators of embryonic development and continue to be expressed throughout postnatal life. The 39 human HOX genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21 [corrected] 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from a primordial homeobox gene. Disorders of limb formation, such as hand-foot-genital syndrome, have been traced to mutations in HOXA13 and HOXD13. Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease. Chromosomal translocations involving the MLL gene, the human homologue of the Drosophila gene trithorax, create fusion genes which exhibit gain of function and are associated with aggressive leukaemias in both adults and children. To date 39 partner genes for MLL have been cloned from patients with leukaemia. Models based on specific translocations of MLL and individual HOX genes are now the subject of intense research aimed at understanding the molecular programs involved, and ultimately the design of chemotherapeutic agents for leukaemia. Investigation of the role of HOX genes in cancer has led to the concept that oncology may recapitulate ontology, a challenging postulate for experimentalists in view of the functional redundancy implicit in the HOX gene network.

The chronic fatigue syndrome: A comparative pathway analysis

In this paper, we introduce a method to detect pathological pathways of a disease. We aim to identify biological processes rather than single genes affected by the chronic fatigue syndrome (CFS). So far, CFS has neither diagnostic clinical signals nor abnormalities that could be diagnosed by laboratory examinations. It is also unclear if the CFS represents one disease or can be subdivided in different categories. We use information from clinical trials, the gene ontology (GO) database as well as gene expression data to identify undirected dependency graphs (UDGs) representing biological processes according to the GO database. The structural comparison of UDGs of sick versus non-sick patients allows us to make predictions about the modification of pathways due to pathogenesis.

Presentism and ontological symmetry

In this paper, I argue that there is an inconsistency between two presentist doctrines: that of ontological symmetry and asymmetry of fixity. The former refers to the presentist belief that the past and future are equally unreal. The latter refers to the A-Theoretic intuition that the past is closed or actual, and the future is open or potential. My position in this paper is that the presentist is unable to account for the temporal asymmetry that is so fundamentally a part of her theory. In Section I, I briefly outline a recent defence of presentism due to Craig, and argue that a flaw in this defence highlights the tension between the presentist's doctrines of ontological symmetry and asymmetry of fixity. In Section II, I undertake an investigation, on the presentist's behalf, in order to determine whether she is capable of reconciling these two doctrines. In the course of the investigation, I consider different asymmetries, other than that of ontology, which might be said fundamentally to constitute temporal asymmetry, and the asymmetry of fixity in particular. In Section III, I also consider whether the presentist is able to avail herself of some of the standard B-Theoretic accounts of the asymmetry of fixity, and argue that she cannot. Finally, I conclude that temporal asymmetry cannot be accounted for (or explained) other than through the postulation of an ontological asymmetry.

Beckett and Performance

The recent interest in genealogical criticism in Beckett Studies, fuelled by the reading notes that Beckett compiled in the 1920’s and 1930’s, has led to a particular focus on Beckett’s formative years, and on the intersections between his work, especially the novels and early criticism, and his intellectual reading. While this has produced much valuable and fascinating matrial, perhaps it is time to return to the works themselves, and especially, to the theatre. Having just published a book on Performing Embodiment in Samuel Beckett’s Drama (London, Routledge, 2010), I would like to develop further the area of presence and performance in Beckett’s theatre. Performance studies and phenomenology have offered new ways of approaching the ontology of performance in Beckett’s theatre, and I intend to analyze this, with particular reference to specific productions of Beckett’s plays. Firstly, I want to look at some of Beckett’s own comments about particular performances / productions (for example in the Barbara Bray correspondence, Trinity College Dublin), and, secondly, to analyze from the perspective / experience of an audience member a number of performances by (mainly Anglophone) ‘Beckett actors’, including Billie Whitelaw and David Warrilow. Drawing on recent discussions of presence and performance (Jane Goodall, Cormac Power), I will offer some reflections on the complexity of presence (of persona and performer, of body and voice) and its haunting power in performances of Beckett’s drama.

On the Problems of Mixing RCTs with Qualitative Research: The Case of the MRC Framework for the Evaluation of Complex Healthcare Interventions

In the perceived hierarchy of research designs, the results from randomized controlled trials are considered to provide the highest level of evidence. Indeed these trials have been upheld as the gold standard in research. The benefits and limitations of the randomized controlled trial as a method of evaluating the effectiveness of healthcare interventions are presented. The article then examines the different levels of complexity within healthcare interventions and the problems this poses in determining effectiveness. In an effort to provide a solution to this problem, the Medical Research Council produced a framework to assist investigators to develop and evaluate complex healthcare interventions. The framework is described with reference to an example of implementing and evaluating protocols for weaning patients in the intensive care unit. The framework is critiqued on the basis that it involves an ambiguous or contradictory ontology, which fails to articulate the relationship between the positivism of randomized controlled trials with the relativism of qualitative approaches. It is concluded that the use of realist strategies in combination with randomized controlled trials provides the most coherent solution to this quandary

The use and limitation of realistic evaluation as a tool for evidence-based practice: a critical realist perspective

In this paper, we assess realistic evaluation’s articulation with evidence-based practice (EBP) from the perspective of critical realism. We argue that the adoption by realistic evaluation of a realist causal ontology means that it is better placed to explain complex healthcare interventions than the traditional method used by EBP, the randomized controlled trial (RCT). However, we do not conclude from this that the use of RCTs is without merit, arguing that it is possible to use both methods in combination under the rubric of realist theory. More negatively, we contend that the rejection of critical theory and utopianism by realistic evaluation in favour of the pragmatism of piecemeal social engineering means that it is vulnerable to accusations that it promotes technocratic interpretations of human problems. We conclude that, insofar as realistic evaluation adheres to the ontology of critical realism, it provides a sound contribution to EBP, but insofar as it rejects the critical turn of Bhaskar’s realism, it replicates the technocratic tendencies inherent in EBP.

The Sound of Becoming: Moving Towards a Virtual Music

In 1985 Jacques Attali proposed a new modality for music. He suggests that there be “not a new music, but a new way of making music... a radically new form of the insertion of music into communication” (Attali 134). What Attali foretold has become a firm reality in contemporary musical practice. One has only to look at any current musical activity to encounter work that relies heavily on real-time interaction and dynamic generation and/or modification of materials. But why is this ontologically different ‘mode of essentially interactive and transformative existence’ (Ziarek 195), this ‘new way of making music’, so attractive to contemporary artists? What is motivating artists to abandon a production model in favor of a model of real-time interactive exploration? I will argue that at the foundation of this new artistic ontology lies Deleuze’s concept of the virtual. It is a recognition of the virtual power of music, that music making can be an act of invention, a process where one can discover something never before experienced.

Soundweaving: Writings on Improvisation

This book consists of eight chapters with writings on improvisation and an introduction by one of the most intriguing improvisers of our generation – Evan Parker.
The initial discussions for this book were carried out during the “Two Thousand + TEN” symposium, which took place on the 6th of November 2010 at the Sonic Arts Research Centre in Belfast. The symposium’s theme was ‘improvisation’. Georgina Born and David Borgo gave keynote addresses, alongside many other excellent speakers, several of who are included in this book.
My contribution is a novel way of editing texts, as I have woven all chapters into an overall piece of writing, interlaced with my own contribution of around 40 pages.

An Integration Methodology for Automated Recurring Cost Prediction using Digital Manufacturing Technology

The need to account for the effect of design decisions on manufacture and the impact of manufacturing cost on the life cycle cost of any product are well established. In this context, digital design and manufacturing solutions have to be further developed to facilitate and automate the integration of cost as one of the major driver in the product life cycle management. This article is to present an integration methodology for implementing cost estimation capability within a digital manufacturing environment. A digital manufacturing structure of knowledge databases are set out and the ontology of assembly and part costing that is consistent with the structure is provided. Although the methodology is currently used for recurring cost prediction, it can be well applied to other functional developments, such as process planning. A prototype tool is developed to integrate both assembly time cost and parts manufacturing costs within the same digital environment. An industrial example is used to validate this approach.

Cosmopolitanism as the existential condition of humanity

Cosmopolitanism as the existential condition of humanity refers to the view that human beings are both transcendent and social. This is argued through another pair of concepts, commonality and difference. If humans are moral, it is because they recognise each other as sharing a basic ontology. But this morality is expressed in the sort of regard that separates ‘me’ from ‘you’. Two aspects of difference are elaborated: foreignness feared as alien but also found in oneself, and alterity as irreducibly other. How can these differences keep us both individual and social?

Association Study of 167 Candidate Genes for Schizophrenia Selected by a Multi-Domain Evidence-Based Prioritization Algorithm and Neurodevelopmental Hypothesis

Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n = 3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein-protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this
ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene Ontology terms related to neurodevelopment. Subsequently, genotypes of 3725 SNPs in 167 genes from a custom Illumina iSelect array were used to evaluate the top ranked vs. hypothesis selected genes. Seventy-three genes were both highly ranked and involved in neurodevelopment (category 1) while 42 and 52 genes were exclusive to neurodevelopment (category 2) or highly ranked (category 3), respectively. The most significant associations were observed in genes PRKG1, PRKCE, and CNTN4 but no individual SNPs were significant after correction for multiple testing. Comparison of the approaches showed an excess of significant tests using the hypothesis-driven neurodevelopment category. Random selection of similar sized genes from two independent genome-wide association studies (GWAS) of schizophrenia showed the excess was unlikely by chance. In a further meta-analysis of three GWAS datasets, four candidate SNPs reached nominal significance. Although gene ranking using integrated sources of prior information did not enrich for significant results in the current experiment, gene selection using an a priori hypothesis (neurodevelopment) was superior to random selection. As such, further development of gene ranking strategies using more carefully selected sources of information is warranted.

Interfacing cellular networks of S. cerevisiae and E. coli: Connecting dynamic and genetic information

Background: In recent years, various types of cellular networks have penetrated biology and are nowadays used omnipresently for studying eukaryote and prokaryote organisms. Still, the relation and the biological overlap among phenomenological and inferential gene networks, e.g., between the protein interaction network and the gene regulatory network inferred from large-scale transcriptomic data, is largely unexplored.

Results: We provide in this study an in-depth analysis of the structural, functional and chromosomal relationship between a protein-protein network, a transcriptional regulatory network and an inferred gene regulatory network, for S. cerevisiae and E. coli. Further, we study global and local aspects of these networks and their biological information overlap by comparing, e.g., the functional co-occurrence of Gene Ontology terms by exploiting the available interaction structure among the genes.

Conclusions: Although the individual networks represent different levels of cellular interactions with global structural and functional dissimilarities, we observe crucial functions of their network interfaces for the assembly of protein complexes, proteolysis, transcription, translation, metabolic and regulatory interactions. Overall, our results shed light on the integrability of these networks and their interfacing biological processes.

Improving the Semantics of Conceptual-Modeling Grammars:A New Perspective on an Old Problem

A core activity in information systems development involves understanding the
conceptual model of the domain that the information system supports. Any conceptual model is ultimately created using a conceptual-modeling (CM) grammar. Accordingly, just as high quality conceptual models facilitate high quality systems development, high quality CM grammars facilitate high quality conceptual modeling. This paper seeks to provide a new perspective on improving the quality of CM grammar semantics. For the past twenty years, the leading approach to this topic has drawn on ontological theory. However, the ontological approach captures just half of the story. It needs to be coupled with a logical approach. We show how ontological quality and logical quality interrelate and we outline three contributions of a logical approach: the ability to see familiar conceptualmodeling problems in simpler ways, the illumination of new problems, and the ability to prove the benefit of modifying CM grammars.

Using SILAC proteomics to investigate the effect of the mycotoxin, alternariol, in the human H295R steroidogenesis model

The mycotoxin alternariol (AOH) is an important contaminant of fruits and cereal products. The current study sought to address the effect of a non-toxic AOH concentration on the proteome of the steroidogenic H295R cell model. Quantitative proteomics based on stable isotope labeling by amino acids in cell culture (SILAC) coupled to 1D-SDS-PAGE-LC-MS/MS was applied to subcellular-enriched protein samples. Gene ontology (GO) and ingenuity pathway analysis (IPA) were further carried out for functional annotation and identification of protein interaction networks. Furthermore, the effect of AOH on apoptosis and cell cycle distribution was also determined by the use of flow cytometry analysis. This work identified 22 proteins that were regulated significantly. The regulated proteins are those involved in early stages of steroid biosynthesis (SOAT1, NPC1, and ACBD5) and C21-steroid hormone metabolism (CYP21A2 and HSD3B1). In addition, several proteins known to play a role in cellular assembly, organization, protein synthesis, and cell cycle were regulated. These findings provide a new framework for studying the mechanisms by which AOH modulates steroidogenesis in H295R cell model. 

The uncritical realism of realist evaluation

This article is a response to Ray Pawson’s critique of critical realism, the philosophy of science elaborated by Roy Bhaskar. I argue with Pawson’s interpretation of critical realism’s positions on both natural and social science and his charges concerning its totalizing ontology, its arrogant epistemology and its naive methodology. The differences between critical realism and realist evaluation are not as significant as Pawson contends. The main differences between the two realisms lie in their approaches to the relationship between social structures and human agency, and between facts and values. I argue that evaluation scientists need to clearly distinguish structure and agency. They should also make their values explicit. The uncritical approach of realist evaluation, combined with its underplaying of the importance of agency, leaves it open to implication in the abuses of bureaucratic instrumentalism.