Silencing E3 Ubiqutin ligase ITCH as a potential therapy to enhance chemotherapy efficacy in p53 mutant neuroblastoma cells

P53 mutations are responsible for drug-resistance of tumour cells which impacts on the efficacy of treatment. Alternative tumour suppressor pathways need to be explored to treat p53- deficient tumours. The E3 ubiquitin ligase, ITCH, negatively regulates the tumour suppressor protein TP73, providing a therapeutic target to enhance the sensitivity of the tumour cells to the treatment. In the present study, two p53-mutant neuroblastoma cell lines were used as in vitro models. Using immunostaining, western blot and qPCR methods, we firstly identified that ITCH was expressed on p53-mutant neuroblastoma cell lines. Transfection of these cell lines with ITCH siRNA could effectively silence the ITCH expression, and result in the stabilization of TP73 protein, which mediated the apoptosis of the neuroblastoma cells upon irradiation treatment. Finally, in vivo delivery of the ITCH siRNA using nanoparticles to the neuroblastoma xenograft mouse model showed around 15–20% ITCH silencing 48 hours after transfection. Our data suggest that ITCH could be silenced both in vitro and in vivo using nanoparticles, and silencing of ITCH sensitizes the tumour cells to irradiation treatment. This strategy could be further explored to combine the chemotherapy/radiotherapy treatment to enhance the therapeutic effects on p53-deficient neuroblastoma

Shaping the future for primary care education and training project. Best practise in education and training strategies for integrated health and social care: a benchmarking tool

This tool has been designed to encourage the systematic evaluation of current services offered in your organisation in relation to education and training. The aim of the benchmarking process is to enable your organisation to judge its ability in six domains: team working, communication, role awareness, personal and professional development, practice development and leadership and team working. Associated with each domain are a set of key questions you should ask about your services in relation to evidencebased ‘best practice’. ‘Best’ practice has been identified and summarised through a systematic review of the literature and through consultation with services users and professionals

The truth-telling motor cortex: Response competition in M1 discloses deceptive behaviour

Neural circuits associated with response conflict are active during deception. Here we use transcranial magnetic stimulation to examine for the first time whether competing responses in primary motor cortex can be used to detect lies. Participants used their little finger or thumb to respond either truthfully or deceitfully regarding facial familiarity. Motor-evoked-potentials (MEPs) from muscles associated with both digits tracked the development of each motor plan. When preparing to deceive, the MEP of the non-responding digit (i.e. the plan corresponding to the truth) exceeds the MEP of the responding digit (i.e. the lie), whereas a mirror-reversed pattern occurs when telling the truth. This give away response conflict interacts with the time of stimulation during a speeded reaction period. Lies can even activate digit-specific cortical representations when only verbal responses are made. Our findings support neurobiological models which blend cognitive decision-making with motor programming, and suggest a novel index for discriminating between honest and intentionally false facial recognition

Teaching the expression of time:A concise framework

ELT materials adopt a system of twelve 'tenses'. Typically, they present three factors as affecting choice of 'tense': event time, event duration and speech time. This is misleading, as many more elements are in play. Their treatment is form-based, giving piecemeal information about the uses of the forms, or providing rules with quite a few exceptions or 'special cases', a practice that tends to confuse learners. This framework is informed by descriptive and theoretical accounts of English. It takes into consideration all the component elements of expressing time in English, including the meaning of verbs and speaker subjectivity. It presents a small number of consistent and flexible guidelines, provides a systematic visual representation of time reference and helps learners put in perspective the information in pedagogical materials

“Filling out the Forms was a Nightmare”: project evaluation and the reflective practitioner in community theatre in contemporary Northern Ireland

Since the Good Friday Agreement of 1998, large sums have been invested in community theatre projects in Northern Ireland, in the interests of conflict transformation and peace building. While this injection of funds has resulted in an unprecedented level of applied theatre activity, opportunities to maximise learning from this activity are being missed. It is generally assumed that project evaluation is undertaken at least partly to assess the degree of success of projects against important social objectives, with a view to learning what works, what does not, and what might work in the future. However, three ethnographic case studies of organisations delivering applied theatre projects in Northern Ireland indicate that current processes used to evaluate such projects are both flawed and inadequate for this purpose. Practitioners report that the administrative work involved in applying for and justifying funding is onerous, burdensome, and occurs at the expense of artistic activity. This is a very real concern when the time and effort devoted to ‘filling out the forms’ does not ultimately result in useful evaluative information. There are strong disincentives for organisations to report honestly on their experiences of difficulties, or undesirable impacts of projects, and this problem is not transcended by the use of external evaluators. Current evaluation processes provide little opportunity to capture unexpected benefits of projects, and small but significant successes which occur in the context of over-ambitious objectives. Little or no attempt is made to assess long-term impacts of projects on communities. Finally, official evaluation mechanisms fail to capture the reflective practice and dialogic analysis of practitioners, which would richly inform future projects. The authors argue that there is a need for clearer lines of communication, and more opportunities for mutual learning, among stakeholders involved in community development. In particular, greater involvement of the higher education sector in partnership with government and non-government agencies could yield significant benefits in terms of optimizing learning from applied theatre project evaluations

The relative influence of neighbourhood incivilities, cognitive social capital, club membership and individual characteristics on positive mental health

Previous research indicates that residents׳ perceptions of their neighbourhoods can have an adverse influence on their health and wellbeing over and above the influence of structural disadvantage. Contrary to most prior research, this study employed an indicator of positive wellbeing and assessed the impact of individual characteristics, perceived social and environmental incivilities, indicators of cognitive and structural social capital, and perceived safety. Analyses of data from a large regional UK representative study (n=8237; 69.64% response rate) found the most influential determinants of wellbeing were physical health problems, age, SES and cognitive social capital. Smaller, significant effects were also found for environmental and social incivilities, and for perceived safety. The effect of cognitive social capital was moderated by age, with a stronger effect found among those aged 65 years and over than among younger participants. Findings indicate that the promotion of positive mental health within communities may be facilitated by efforts to foster a greater sense of belonging among residents, and that older adults may benefit most from such efforts