Muscle-specific mutations accumulate with aging in critical human mtDNA control sites for replication.

The recently discovered aging-dependent large accumulation of point mutations in the human fibroblast mtDNA control region raised the question of their occurrence in postmitotic tissues. In the present work, analysis of biopsied or autopsied human skeletal muscle revealed the absence or only minimal presence of those mutations. By contrast, surprisingly, most of 26 individuals 53 to 92 years old, without a known history of neuromuscular disease, exhibited at mtDNA replication control sites in muscle an accumulation of two new point mutations, i.e., A189G and T408A, which were absent or marginally present in 19 individuals younger than 34 years. These two mutations were not found in fibroblasts from 22 subjects 64 to 101 years of age (T408A), or were present only in three subjects in very low amounts (A189G). Furthermore, in several older individuals exhibiting an accumulation in muscle of one or both of these mutations, they were nearly absent in other tissues, whereas the most frequent fibroblast-specific mutation (T414G) was present in skin, but not in muscle. Among eight additional individuals exhibiting partial denervation of their biopsied muscle, four subjects >80 years old had accumulated the two muscle-specific point mutations, which were, conversely, present at only very low levels in four subjects <or =40 years old. The striking tissue specificity of the muscle mtDNA mutations detected here and their mapping at critical sites for mtDNA replication strongly point to the involvement of a specific mutagenic machinery and to the functional relevance of these mutations.

Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline.

Abstract A classic physiologic response to hypoxia in humans is the up-regulation of the ERYTHROPOIETIN (EPO) gene, which is the central regulator of red blood cell mass. The EPO gene, in turn, is activated by hypoxia inducible factor (HIF). HIF is a transcription factor consisting of an alpha subunit (HIF-alpha) and a beta subunit (HIF-beta). Under normoxic conditions, prolyl hydroxylase domain protein (PHD, also known as HIF prolyl hydroxylase and egg laying-defective nine protein) site specifically hydroxylates HIF-alpha in a conserved LXXLAP motif (where underlining indicates the hydroxylacceptor proline). This provides a recognition motif for the von Hippel Lindau protein, a component of an E3 ubiquitin ligase complex that targets hydroxylated HIF-alpha for degradation. Under hypoxic conditions, this inherently oxygen-dependent modification is arrested, thereby stabilizing HIF-alpha and allowing it to activate the EPO gene. We previously identified and characterized an erythrocytosis-associated HIF2A mutation, G537W. More recently, we reported two additional erythrocytosis-associated HIF2A mutations, G537R and M535V. Here, we describe the functional characterization of these two mutants as well as a third novel erythrocytosis-associated mutation, P534L. These mutations affect residues C-terminal to the LXXLAP motif. We find that all result in impaired degradation and thus aberrant stabilization of HIF-2alpha. However, each exhibits a distinct profile with respect to their effects on PHD2 binding and von Hippel Lindau interaction. These findings reinforce the importance of HIF-2alpha in human EPO regulation, demonstrate heterogeneity of functional defects arising from these mutations, and point to a critical role for residues C-terminal to the LXXLAP motif in HIF-alpha.

Confined Site Construction: A qualitative investigation of critical issues affecting management of Health and Safety

The construction industry is inherently risky, with a significant number of accidents and disasters occurring, particularly on confined construction sites. This research investigates and identifies the various issues affecting successful management of health and safety in confined construction sites. The rationale is that identifying the issues would assist the management of health and safety particularly in inner city centres which are mostly confined sites. Using empiricism epistemology, the methodology was based on qualitative research approach by means of multiple case studies in three different geographical locations of Ireland, UK and USA. Data on each case study were collected through individual interviews and focus group discussion with project participants. The findings suggest that three core issues are the underlying factors affecting management of health and safety on confined construction sites. It include, (i) lack of space, (ii) problem of co-ordination and management of site personnel, and (iii) overcrowding of workplace. The implication of this is that project teams and their organisations should see project processes from a holistic point of view, as a unified single system, where quick intervention in solving a particular issue should be the norm, so as not to adversely affect interrelated sequence of events in project operations. Proactive strategies should be devised to mitigate these issues and may include detail project programming, space management, effective constructability review and efficient co-ordination of personnel, plant and materials among others. The value of this research is to aid management and operation of brownfield sites by identifying issues impacting on health and safety management in project process.

Struggles against Injustice:: Contemporary Critical Theory and Political Violence

This article investigates a significant problem in contemporary critical theory, namely its failure to address effectively the possibility that a campaign of political violence may be a legitimate means of fighting grave injustice. Having offered a working definition of ‘political violence’, I argue that critical theory should be focused on experiences of injustice rather than on ideals of justice. I then explore the reasons as to why, save for some intriguing remarks on retrospective legitimation, Jürgen Habermas has not addressed this issue directly. While Axel Honneth's recognition theory may have greater potential here, the absence of explicit consideration of the matter by him leaves considerable work to do. I introduce five questions in the concluding section that provide a starting point in setting out an appropriately stringent, normative test for claims that support violent action against injustice.

A Review of Meditation in the Irish Construction Industry: Critical Success Factors in Competencies and Processes

The construction industry notoriously excels at dispute creation – both in Ireland and world wide. This paper exams mediation in the Irish construction industry based around critical success factors in the competencies and processes required by mediators operating in the construction industry. Through conducting the relevant analysis, it was possible to extract and outline the resulting critical success factors in process and competencies of mediators in the Irish construction industry. This was achieved through a review of the literature, followed by detailed interviews from industry experts to elicit and highlight the core competencies required. To aid in the study, qualitative analysis using mind mapping software was adopted, thus assisting the identification of the key factors. Following analysis, facilitative mediation was identified as best suited for the industry in question; recommendations and experience were key for mediator selection and five and six factors were identified for mediator skills and mediation critical success factors respectively. The results returned are similar to those determined by authors in other countries and provide a good reference point for the development the industry. By following the findings of this report mediators and parties in dispute can improve processes and be more successful in outcomes. In this study the author shows that mediation is an effective and appropriate method of resolving disputes within the Irish construction industry.

Asset Tracking in Critical Power Communications Infrastructures using Passive Techniques

Active network scanning injects traffic into a network and observes responses to draw conclusions about the network. Passive network analysis works by looking at network meta data or by analyzing traffic as it traverses a fixed point on the network. It may be infeasible or inappropriate to scan critical infrastructure networks. Techniques exist to uniquely map assets without resorting to active scanning. In many cases, it is possible to characterize and identify network nodes by passively analyzing traffic flows. These techniques are considered in particular with respect to their application to power industry critical infrastructure.

What is the Point of Copyright History?:Reflections on Copyright at Common law in 1774 by H. Tomás Gómez-Arostegui

Copyright history has long been a subject of intense and contested enquiry. Historical narratives about the early development of copyright were first prominently mobilised in eighteenth century British legal discourse, during the so-called Battle of the Booksellers between Scottish and London publishers. The two landmark copyright decisions of that time – Millar v. Taylor (1769) and Donaldson v. Becket (1774) – continue to provoke debate today. The orthodox reading of Millar and Donaldson presents copyright as a natural proprietary right at common law inherent in authors. Revisionist accounts dispute that traditional analysis. These conflicting perspectives have, once again, become the subject of critical scrutiny with the publication of Copyright at Common Law in 1774 by Prof Tomas Gomez-Arostegui in 2014, in the Connecticut Law Review ((2014) 47 Conn. L. Rev. 1) and as a CREATe Working Paper (No. 2014/16, 3 November 2014).

Taking Prof Gomez-Arostegui’s extraordinary work in this area as a point of departure, Dr Elena Cooper and Professor Ronan Deazley (then both academics at CREATe) organised an event, held at the University of Glasgow on 26th and 27th March 2015, to consider the interplay between copyright history and contemporary copyright policy. Is Donaldson still relevant, and, if so, why? What justificatory goals are served by historical investigation, and what might be learned from the history of the history of copyright? Does the study of copyright history still have any currency within an evidence-based policy context that is increasingly preoccupied with economic impact analysis?

This paper provides a lasting record of these discussions, including an editorial introduction, written comments by each of the panelists and Prof. Gomez-Arostegui and an edited transcript of the Symposium debate.

What is the Point of Copyright History?

Copyright history has long been a subject of intense and contested enquiry, and has once again become the subject of critical scrutiny with the publication of "Copyright at Common Law in 1774" by Prof Tomas Gomez-Arostegui in the Connecticut Law Review ((2014) 47 Conn. L. Rev. 1).
This online resource documents two events organised to explore the impact of "Copyright at Common Law in 1774". It incorporates a public lecture by Prof Gomez-Arostegui, and the full record of a one-day symposium of international experts debating the implications of Gomez-Arostegui's scholarship in this domain.

Ultrasound in undergraduate medical education: A systematic and critical review

Introduction: Point-of-care ultrasound (POCUS) use in clinical care is growing rapidly, and advocates have recently proposed the integration of ultrasound into undergraduate medical education (UME). The evidentiary basis for this integration has not been evaluated critically or systematically. In this study, we conducted a critical and systematic review framed by the rationales enumerated by advocates of ultrasound in UME in academic publications.

Methods: This research was conducted in two phases. First, the dominant discursive rationales for the integration of ultrasound in UME were identified using techniques from Foucauldian critical discourse analysis (CDA) from an archive of 403 academic publications. We then sought empirical evidence in support of theses rationales, using a critical synthesis methodology also adapted from CDA.

Results: We identified four dominant discursive rationales, with different levels of evidentiary support. Ultrasound was not demonstrated to improve students’ understanding of anatomy. The benefit of ultrasound in teaching physical examination was inconsistent,and rests on minimal evidence. With POCUS, students’ diagnostic accuracy was improved for certain pathologies, but findings were inconsistent for others. Finally, the rationale that ultrasound training in UME will improve quality of patient care was difficult to evaluate.

Discussion: Our analysis has shown that the frequently repeated rationales for the integration of ultrasound in UME are not supported by a sufficient base of empirical research. The repetition of these dominant discursive rationales in academic publications legitimizes them and may preclude further primary research. Since the value of clinical ultrasound use by medical students remains unproven, educators must consider whether the associated financial and temporal costs are justified or whether more research is required.