The Role of the p14ARF Tumour Suppressor in Promoting Apoptosis

The incidence of melanoma has risen dramatically during the past three decades, yet there has been little improvement in effective treatments for this intractable and aggressive disease. Melanoma tumours are notoriously resistant to apoptosis, a cell suicide program that is activated by most cancer therapies. This thesis explores the role of the melanoma susceptibility gene product p14ARF in promoting cell cycle arrest and apoptosis, in order to resolve the impact of this tumour suppressor in melanomagenesis and melanoma susceptibility. The p14ARF tumour suppressor gene is mutated in almost half of all cancers, and germline mutations in p14ARF confer a greatly increased risk of developing melanoma. The primary function of p14ARF is to relay oncogenic signals to p53, a central regulator of cellular response to stress. There is conflicting evidence regarding the role of p14ARF in promoting apoptosis. Much of the current evidence is based on murine studies, which may not translate accurately to humans due to important differences in animal physiology and the primary sequence and functions of the mouse and human ARF proteins. Furthermore, results from previous studies are often compounded by supra-physiological expression of p14ARF, and are complicated by the fact that p14ARF shares its genomic sequence with the p16INK4a tumour suppressor gene. This study demonstrates that p14ARF expression in human cancer and primary cell lines promotes rapid p53-dependent cell cycle arrest, rather than apoptosis. As p14ARF expression did not induce apoptosis, we investigated if p14ARF could modulate the sensitivity of a cell to apoptosis induced by cytotoxic agents. Using a p14ARF-inducible U2OS osteosarcoma cell line model, we examined the impact of p14ARF expression on the apoptotic response of the cell to a panel of thirteen cytotoxic agents. p14ARF expression increased apoptosis caused by a sub-set of agents, including trichostatin A, sodium butyrate, DRB, Adriamycin and UVB radiation. p14ARF-mediated chemosensitivity was p53- and caspase-dependent, and involved the loss of mitochondrial potential. While loss of mitochondrial potential was dependent on p53, it was not blocked by caspase inhibition, demonstrating that caspases play a role downstream of mitochondrial depolarisation. Inhibition of individual components of the apoptotic program showed that p14ARF-mediated chemosensitivity was not strictly dependent on the pro-apoptotic Bax or Fas proteins. We also investigated whether p14ARF could sensitise melanoma to chemotherapeutics in vivo. We investigated the expression level of p14ARF, p16INK4a and MITFm and mutation status of B-RAF, N-RAS and PTEN in melanomas from 30 patients that had undergone isolated limb infusion - a palliative therapeutic strategy that results in much higher response rates than systemic treatment. Expression of p14ARF did not predict response to the drugs actinomycin D and melphalan . Instead, high expression of p16INK4a and presence of activating N-RAS mutation were independent predictors of response to high doses of these chemotherapeutic drugs. This work suggests that p14ARF analogues may be beneficial adjuncts in cancer therapy, but are unlikely to be effective as single agents. Additionally, p14ARF mimetics will only be effective in tumours with intact p53 signalling. Melanomas frequently carry functional p53, and may be susceptible to this mode of treatment providing the apoptotic pathway downstream of p53 is intact or can be restored

Ghost hunting in the broken archives:Re-historicizing digital education in an institutional context

Digital education is often presented as breaking from tradition. A failure to account for how digital education emerges from historical institutional activity is problematic insofar as this activity continues to circulate through the present and future, appearing and disappearing in often unexpected ways. Using Derrida’s hauntology as a theoretical lens, this paper traces how a digital education initiative at the University of Edinburgh in 2003 carried through to the creation of a course to train teachers to teach online in 2019, which in turn informed the university’s response to the pandemic in 2020. Working in a broadly autoethnographic way alongside archival document analysis, several findings emerged. First, hauntology provides a mechanism for institutions to trace their own histories and to note how these histories, often hidden in archives or carried forward into the present by hosts, inform their present and future trajectories. Second, broken archives, those that have ceased to function as active repositories but are disconnected from institutional domains and ontologies, shut due to absent gatekeepers, or merely forgotten, contribute​ to the sudden and often unexpected emergence of hauntings in present and future trajectories. Third, curation of the archive is an act of reinterpretation, one that troubles historical narratives and introduces new hauntings. All these findings assert a re-historicizing of digital education by emphasising the hauntings from the past that inform its emergent present and contested future, countering many of the ahistorical imaginaries of digital education

Grey and white matter differences in Chronic Fatigue Syndrome : A voxel-based morphometry study

Conflicts of interest and source of funding The authors declare no conflicts of interest. This research was funded by the Medical Research Council (MR/J002712/1). AF is supported by Research Capability Funding from the Newcastle upon Tyne Hospitals NHS Foundation Trust and the Northumberland, Tyne and Wear NHS Foundation Trust.Peer reviewedPublisher PD

Improving productivity with dairy farm performance

How productive can a dairy farm be? What options are available to dairy farmers to increase their productivity and profitability? How can you reduce milk production costs effectively? These are the kinds of questions that dairy farmers are, or should be, asking leading up to and immediately after deregulation. These questions, and many more, can be answered by participating in Agriculture Western Australia\u27s (AGWEST) Dairy Farm Performance (DFP) Program. David Windsor, Ken Crawford, Stuart Gallagher and Vicki Staines report on DFP and the benefits being generated for dairy farmers in Western Australia

The chronology and tectonic style of landscape evolution along the elevated Atlantic continental margin of South Africa resolved by joint apatite fission track and (U-Th-Sm)/He thermochronology

Atlantic-type continental margins have long been considered “passive” tectonic settings throughout the entire postrift phase. Recent studies question the long-term stability of these margins and have shown that postrift uplift and reactivation of preexisting structures may be a common feature of a continental margin's evolution. The Namaqualand sector of the western continental margin of South Africa is characterized by a ubiquitously faulted basement but lacks preservation of younger geological strata to constrain postrift tectonic fault activity. Here we present the first systematic study using joint apatite fission track and apatite (U-Th-Sm)/He thermochronology to achieve a better understanding on the chronology and tectonic style of landscape evolution across this region. Apatite fission track ages range from 58.3 ± 2.6 to 132.2 ± 3.6 Ma, with mean track lengths between 10.9 ± 0.19 and 14.35 ± 0.22 µm, and mean (U-Th-Sm)/He sample ages range from 55.8 ± 31.3 to 120.6 ± 31.4 Ma. Joint inverse modeling of these data reveals two distinct episodes of cooling at approximately 150–130 Ma and 110–90 Ma with limited cooling during the Cenozoic. Estimates of denudation based on these thermal histories predict approximately 1–3 km of denudation coinciding with two major tectonic events. The first event, during the Early Cretaceous, was driven by continental rifting and the development and removal of synrift topography. The second event, during the Late Cretaceous, includes localized reactivation of basement structures as well as regional mantle-driven uplift. Relative tectonic stability prevailed during the Cenozoic, and regional denudation over this time is constrained to be less than 1 km

Safety margins and adaptive capacity of vegetation to climate change

Vegetation is composed of many individual species whose climatic tolerances can be integrated into spatial analyses of climate change risk. Here, we quantify climate change risk to vegetation at a continental scale by calculating the safety margins for warming and drying (i.e., tolerance to projected change in temperature and precipitation respectively) across plants sharing 100km × 100km grid cells (locations). These safety margins measure how much warmer, or drier, a location could become before its ‘typical’ species exceeds its observed climatic limit. We also analyse the potential adaptive capacity of vegetation to temperature and precipitation change (i.e., likelihood of in situ persistence) using median precipitation and temperature breadth across all species in each location. 47% of vegetation across Australia is potentially at risk from increases in mean annual temperature (MAT) by 2070, with tropical regions most vulnerable. Vegetation at high risk from climate change often also exhibited low adaptive capacity. By contrast, 2% of the continent is at risk from reductions in annual precipitation by 2070. Risk from precipitation change was isolated to the southwest of Western Australia where both the safety margin for drier conditions in the typical species is low, and substantial reductions in MAP are projected

Creating hope in dystopia: Utopia as Method as social pedagogy in early childhood studies

Those who choose to engage with the academic world of early childhood are frequently caught between encouraging students to advocate for children and contribute to the construction of a good life and navigating the regulatory frameworks that shape future practice. In short, we must prepare students for the highly skilled work of supporting people who live their lives in day-to-day actions that are underpaid, under-resourced and overlooked. Those who prepare students for this reality are tasked with developing programmes that both instil hope and pragmatism that will sustain them when faced with these everyday realities. This article outlines how the authors addressed this through an adapted use of Utopia as Method in a module on an early childhood degree. By following its distinct modes, students are guided to position themselves not as passive observants of a childhood that is socially constructed around them, but as social and political actors engaged with making human beings human. Among other issues the article evaluates the intersection between social pedagogy, utopia and the future of early childhood. Based on explorations undertaken for this article, we argue that the imaginative reconstruction of childhood through higher education is at ease with the values and purpose of social pedagogy. We reflect that, while the method employed as part of a module was useful in terms of personal development and future-oriented practice, the need to include children’s voices is yet to be developed

Common Vigilance: A Perspective On the Role of the Community in Safeguarding Children

Since the Children Act 2004 (HMG, 2004), it has become commonplace to read that safeguarding is everyone’s responsibility. No distinction is made, though, between ‘everyone’ individually and ‘everyone’ collectively, with the result that efforts to unpick exactly how everyone is able to respond to children’s safeguarding and protection needs are frustrated. This chapter asks whether or not ‘community’ is a useful concept to help organise these efforts and to prevent the slogan from unhelpfully collapsing the issue of responsibility together. It considers Bronfenbrenner’s ecological model (Bronfenbrenner, 1979) and bio-ecological model (Bronfenbrenner and Ceci, 1994) to understand how community might animate child protection efforts at a level beyond the scope of distinct families but without encompassing statutory responsibility either. Bourdieu’s concept of ‘habitus’ (Shusterman, 1999) is used to examine the social worlds of children in their respective communities to understand the risk and vulnerabilities of children, on the one hand, and the safeguarding responses by concerned adults in the community. Recent analysis of serious case reviews (SCRs) and inquiries relating to child sexual exploitation to understand how the ‘community’ inform the discussion of communitylevel communication regarding common concerns for children’s safety and well-being. The chapter proposes that common vigilance may serve as a more robust concept than does community in efforts to produce social conditions that secure children’s safety from maltreatment. The chapter encourages you to consider your position as a professional who embodies interest in children’s safety from harm as well as compliance with statutory procedures and expectations of competence

The articulation of enkinaesthetic entanglement

In this article I present an argument for the necessary co-articulation of meaning within our felt enkinaesthetic engagement with our world. The argument will be developed through a series of stages, the first of which will be an elaboration of the notion of articulation of and through the body. This will be followed by an examination of enkinaesthetic experiential entanglement and the role it plays in rendering our world meaningful and our actions values-realising. At this stage I will begin to extend Husserl’s notion of intentional transgression to the enkinaesthetic sphere of lived experience, and in support of this claim I will examine the theoretical and practical work of osteopathic manual listening [Gens & Roche 2014] and the ‘felt sense’ in focusing [Gendlin] which makes possible a shift from a somatic articulation to a semantic, and potentially conceptual, one. Throughout, my position will be compatible with Merleau-Ponty’s claim that “Whenever I try to understand myself, the whole fabric of the perceptible world comes too, and with it comes the others who are caught in it.” [Merleau-Ponty 1964a, p.15]