Identification of the Amino Acids 300–600 of IRS-2 as 14-3-3 Binding Region with the Importance of IGF-1/Insulin-Regulated Phosphorylation of Ser-573

Phosphorylation of insulin receptor substrate (IRS)-2 on tyrosine residues is a key event in IGF-1/insulin signaling and leads to activation of the PI 3-kinase and the Ras/MAPK pathway. Furthermore, phosphorylated serine/threonine residues on IRS-2 can induce 14-3-3 binding. In this study we searched IRS-2 for novel phosphorylation sites and investigated the interaction between IRS-2 and 14-3-3. Mass spectrometry identified a total of 24 serine/threonine residues on IRS-2 with 12 sites unique for IRS-2 while the other residues are conserved in IRS-1 and IRS-2. IGF-1 stimulation led to increased binding of 14-3-3 to IRS-2 in transfected HEK293 cells and this binding was prevented by inhibition of the PI 3-kinase pathway and an Akt/PKB inhibitor. Insulin-stimulated interaction between endogenous IRS-2 and 14-3-3 was observed in rat hepatoma cells and in mice liver after an acute insulin stimulus and refeeding. Using different IRS-2 fragments enabled localization of the IGF-1-dependent 14-3-3 binding region spanning amino acids 300–600. The 24 identified residues on IRS-2 included several 14-3-3 binding candidates in the region 300–600. Single alanine mutants of these candidates led to the identification of serine 573 as 14-3-3 binding site. A phospho-site specific antibody was generated to further characterize serine 573. IGF-1-dependent phosphorylation of serine 573 was reduced by inhibition of PI 3-kinase and Akt/PKB. A negative role of this phosphorylation site was implicated by the alanine mutant of serine 573 which led to enhanced phosphorylation of Akt/PKB in an IGF-1 time course experiment. To conclude, our data suggest a physiologically relevant role for IGF-1/insulin-dependent 14-3-3 binding to IRS-2 involving serine 573

Many quantitative trait loci for feather growth in an F broiler × layer cross collocate with body weight loci

1. A genome-wide scan of 467 F progeny of a broiler x layer cross was conducted to identify quantitative trait loci (QTL) affecting the rate of growth of the tail, wing and back feathers, and the width of the breast feather tract, at three weeks of age. 2. Correlations between the traits ranged from 0·36 to 0·61. Males had longer tail and wing feathers and shorter back feathers than females. Breast feather tract width was greater in females than males. 3. QTL effects were generally additive and accounted for 11 to 45% of sex average feather lengths of the breeds, and 100% of the breast feather tract width. Positive and negative alleles were inherited from both lines, whereas the layer allele was larger than the broiler allele after adjusting for body weight. 4. A total of 4 genome-significant and 4 suggestive QTL were detected. At three or 6 weeks of age, 5 of the QTL were located in similar regions as QTL for body weight. 5. Analysis of a model with body weight at three weeks as a covariate identified 5 genome significant and 6 suggestive QTL, of which only two were coincident with body weight QTL. One QTL for feather length at 148 cM on GGA1 was identified at a similar location in the unadjusted analysis. 6. The results suggest that the rate of feather growth is largely controlled by body weight QTL, and that QTL specific for feather growth also exist

Constitutive phosphorylation of MDC1 physically links the MRE11–RAD50–NBS1 complex to damaged chromatin

The MRE11–RAD50–Nijmegen breakage syndrome 1 (NBS1 [MRN]) complex accumulates at sites of DNA double-strand breaks (DSBs) in microscopically discernible nuclear foci. Focus formation by the MRN complex is dependent on MDC1, a large nuclear protein that directly interacts with phosphorylated H2AX. In this study, we identified a region in MDC1 that is essential for the focal accumulation of the MRN complex at sites of DNA damage. This region contains multiple conserved acidic sequence motifs that are constitutively phosphorylated in vivo. We show that these motifs are efficiently phosphorylated by caseine kinase 2 (CK2) in vitro and directly interact with the N-terminal forkhead-associated domain of NBS1 in a phosphorylation-dependent manner. Mutation of these conserved motifs in MDC1 or depletion of CK2 by small interfering RNA disrupts the interaction between MDC1 and NBS1 and abrogates accumulation of the MRN complex at sites of DNA DSBs in vivo. Thus, our data reveal the mechanism by which MDC1 physically couples the MRN complex to damaged chromatin

Cultural values, moral sentiments and the fashioning of gendered migrant identities

The promotion of British cultural values to which all citizens can and should sign up to has taken on unprecedented urgency and momentum in political and public discourses. This paper explores the meanings and values attached to contemporary forms of Britishness from the perspective of migrant refugee women, and outlines the conflicting interpretations and expectations of different projects of feminine citizenship. Drawing on empirical research it suggests that gendered migrant identities and values are formed and performed in relation to real and imagined understanding of British (white) heterosexual women and can be seen, at least in part, as asserting moral value and distinctiveness. The women invoked migrant cultural pride in the form of caring, community, close family ties and heterosexuality to claim recognition and resist the lack of moral value ascribed to migrant identities. However, this is achieved through a re-inscription of gender identities in which heterosexuality and sexual restraint become technologies of regulation and control

Effect of increasing fruit and vegetable intake by dietary intervention on nutritional biomarkers and attitudes to dietary change : a randomised trial

This work was funded by The Scottish Government Rural and Environmental Science and Analytical Sciences Division (RESAS) and supported by the Rank Prize Funds.Peer reviewedPublisher PD

[Editorial] Migration, adult education and learning

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British citizenship, gender and migration: the containment of cultural differences and the stratification of belonging

Debates about integration, British values and identity, who can belong and who can become a citizen, have been fuelled by concerns about growing cultural diversity in the United Kingdom. To promote a shared sense of national identity and claim a universal and normative citizen subject, the UK government, along with many other western nations, has introduced compulsory citizenship and language testing. This article traces and critiques the evolution of the British citizenship test since its introduction in 2005 and argues that the regime fails to recognise the gendered and segmented nature of migration, and functions as a silent and largely invisible mechanism of civic stratification and control. Drawing on Home Office data, it is argued that citizenship testing enables the government to cherry pick migrants who conform to an idealised citizen subject, while containing cultural difference by excluding others, particularly women, who are tolerated but remain symbolic non-citizens

"More than just a medical student”: a mixed methods exploration of a structured volunteering programme for undergraduate medical students

Background As a result of the COVID-19 pandemic Imperial College School of Medicine developed a structured volunteering programme involving 398 medical students, across eight teaching hospitals. This case study aims to illuminate the experiences of volunteers, mechanisms of learning and draw lessons for future emergencies and curriculum improvements. Methods Using an illuminative approach to evaluation we invited all volunteers and supervisors to complete a mixed-methods survey. This gathered nominal demographic information and qualitative data related to motivations, experiences, insights into learning, processual and contextual factors. Qualitative responses were coded, thematically organised, and categorised into an overarching framework. Mann-Whitney U tests determined whether volunteers’ overall rating of the experience varied according to demographic features and modulating factors. Spearman’s rank correlation assessed the relationship between aspects of induction and supervision, and overall volunteering rating. Follow up interviews were carried out with students to check back findings and co-create conclusions. Results Modulating factors identified through thematic analysis include altruistic motivation, engaged induction and supervision, feeling valued, having responsibility and freedom from the formal curriculum. Statistically significant positive correlations are identified between volunteers overall rating and being a year 1 or 2 student, ability to discuss role and ask questions during induction, being male, and having regular meetings and role support from supervisors. Qualitatively reported impacts include improved wellbeing, valuable contribution to service and transformative learning. Transformative learning effects included reframing of role within the multidisciplinary team, view of effective learning and view of themselves as competent clinicians. The number of weeks, number of shifts per week, and the role the volunteers performed, did not significantly impact experiences. Conclusions While acknowledging the uniqueness of the situation presented by the first wave COVID-19, we suggest the features of a successful service-learning programme include: a learner-centred induction, engaged and appreciative supervisors, and the entrustment of students with meaningful work with reciprocal benefits to services. Programmes in similar settings may find that 1) volunteering is best appreciated in years 1 or 2, 2) students with altruistic motivations and meaningful work may flourish without formal outcomes and assessments, and 3) that female volunteers may experience emergency learning differently to men

Bring a plate: facilitating experimentation in the Welcome Dinner Project

Drawing on in-depth empirical research, we explore a project called The Welcome Dinner (WDP). The WDP aims to bring together ‘newly arrived’ people and ‘established Australians’ to meet and ‘share stories’ over a potluck meal in ‘the comfort of their own home’. The purpose is to create meaningful connections, new friendships and social solidarities. In this paper, we focus on the micro-contexts of the dinners and the minute activities and techniques that facilitators use in hosting. Our aim is not to analyse the effects of the project but rather the design and meaning of the activities. As a form of ‘designed everyday multiculturalism’, focused on welcoming new arrivals to Australia, it takes effort, skill and labour to manage the contact between different cultural groups over organised meals. Thus, facilitators take over the hosting of the lunches and dinners to run activities, which are imagined to lubricate social dynamics and relations, and produce convivial commensal affects and behaviours. Drawing on theories of training activities as embodied and cognitive experimentations, which enable new knowledge practices and social relations, we analyse field notes and interviews about the facilitation, structure and activities at the WDP home dinners