Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation

FcRI activation of mast cells is thought to involve Lyn and Syk kinases proximal to the receptor and the signaling complex organized by the linker for activation of T cells (LAT). We report here that FcRI also uses a Fyn kinase-dependent pathway that does not require Lyn kinase or the adapter LAT for its initiation, but is necessary for mast cell degranulation. Lyn-deficiency enhanced Fyn-dependent signals and degranulation, but inhibited the calcium response. Fyn-deficiency impaired degranulation, whereas Lyn-mediated signaling and calcium was normal. Thus, FcRI-dependent mast cell degranulation involves cross-talk between Fyn and Lyn kinases.

HIF-2alpha Associated Familial Erythrocytosis Supports the PHD2-HIF2-alpha-VHL Axis as the Major Regulator of Erythropoietin Production

Transcriptionally erythropoietin (Epo) synthesis is tightly regulated by the hypoxia inducible factor (HIF), which is composed of one alpha and one beta subunit that are constitutively expressed. The beta subunit is non-variable, but three different alpha subunits give rise to three isoforms of HIF. The alpha subunit is proteasomally regulated in the presence of oxygen by hydroxylation of the proline in the LXXLAP motif of the oxygen dependent degradation (ODD) domain of HIFalpha, catalysed by members of the prolyl hydroxylase domain (PHD) family of enzymes. This allows the von Hippel Lindau (VHL) protein to associate with the alpha subunit, which is subsequently tagged with ubiquitin and degraded by the proteasome. Any defect in the oxygen sensing pathway that allows the alpha subunit to escape proteasomal regulation leads to elevated expression of HIF target genes.

Recently mutations in both VHL and PHD2 have been identified in a cohort of patients with erythrocytosis, but no mutations were found in the ODD domain of HIF1alpha. Instead, investigation of the homologous region in HIF-2alpha revealed four different mutations, Pro534Leu, Met535Val, Gly537Arg and Gly537Trp in seven individuals/families. Affected individuals presented at a young age with elevated serum Epo. Several individuals have a clinical history of thrombosis, but no evidence of a von Hippel Lindau-like syndrome.

To define how the four mutations relate to the erythrocytosis phenotype functional assays were performed in vitro. Binding of PHD2 to the four HIF-2alpha mutants was impaired to varying degrees, with both the Gly537 mutants showing the greatest reduction. The association of VHL with the hydroxylated Met535Val mutant peptide was similar to wild type HIF- 2alpha, but was decreased in the other three HIF-2alpha mutants. Expression of three HIF- 2alpha target genes, adrenomedullin, NDRG1 and VEGF, was significantly up-regulated in cells stably transfected with the mutants under normoxia compared to wild type HIF-2alpha. Mutations in the ODD domain of HIF-2alpha disrupt proteasomal regulation by reducing the association with PHD2 and hence hydroxylation. Furthermore the binding of VHL is also impaired, even when HIF-2alpha is hydroxylated. Examination of the three-dimensional structure of hydroxylated HIF-1alpha bound to VHL confirms that amino acids close to site of hydroxylation (Pro-531 in isoform 2) are important for this association. These observations, together with recent studies utilising murine models of erythrocytosis, support the PHD2-HIF-2alpha-VHL axis as the major regulator of erythropoietin.

Evidence from a Baseline Study of Teachers and Young People in Northern Ireland: Implications for Peace Education.

Peace education initiatives in schools are often based on social psychological theories assuming that social identity affects ingroup and outgroup attitudes and, in turn, behaviors relating to relevant outgroups. However, research evidence on the role of young people’s social identity has often failed to take account of different social identity dimensions or to conceptualise outgroup behavior in the context of young people’s understandings of the social world. While recent research relating to bullying and bystander behavior amongst young people has addressed the latter point, this has rarely been considered in conjunction with a differentiated view of social identity. This paper is therefore distinctive as it will address the role of social identity dimensions with regards to behavior as captured in bystander scenarios relating to intergroup discrimination. This is particularly important in the context of divided societies, where peace education initiatives are crucial in promoting positive community relations for the future and where such initiative may be hampered by communities’ concerns about loss of identity and hardened intergroup attitudes. Furthermore, previous research frequently highlighted teachers’ fears to tackle outgroup attitudes in the classroom, especially in contexts where pupils and the wider school community are seen as entrenched in community divisions (Hughes, Donnelly, Hewstone, Gallagher & Carlisle, 2010). However, there is no research investigating the relationship between pupils’ attitudes and teacher confidence to talk about such issues in the classroom, which is explored in this paper.

In the context of Northern Ireland, a divided society emerging from sectarian conflict, social identity, outgroup attitudes and outgroup behaviours have been key concepts addressed by peace educators for many years. Building on this work, this paper provides a detailed picture of young people’s strength of group identification and their willingness to explore ingroup perspectives, sectarian attitudes and their reported willingness to challenge sectarian bullying. Using data from a baseline survey, which forms part of a randomized control trial investigating the effect of an educational intervention aimed to promote reconciliation, the sample involved young people of different denominational backgrounds, attending separate school sectors. The baseline data will be used to compare with post intervention data. Therefore, the data and its findings would be of particular interest to educators and policy makers in other European countries who are working to develop peace education interventions in societies emerging from conflict. Additionally, this paper considers the results from a baseline teacher survey, collected before training and teaching of the intervention began. The teacher survey focused on confidence in tackling sectarian issues in the classroom, previous experience of teaching such issues and their hopes and concerns for the reconciliation intervention.

This paper therefore set out to investigate the relationship between dimensional concept of social identity, sectarian attitudes and pupils’ reported willingness to challenge sectarian bullying and to compare this with their teachers’ attitudes to teaching about sectarian issues in the classroom.



Method

The pupil sample included 35 primary and post-primary schools and about 800 pupils from 8-11 years old who completed an online questionnaire in December 2011 and January 2012. Main instruments for young people’s survey included an adapted version of the Multi-ethnic identity measure (Phinney, 1992) incorporating the dimensions identity affirmation and exploration, outgroup attitude scales, including an adaptation of the social distance measure (Bogardus, 1947), as well as a measure adapted from Palmer and Cameron (2011) involving scenarios to capture pupils’ intentions in bystander situations relating to intergroup discrimination. Results are analysed using regression analysis and take account of potential gender and religious differences. The teacher questionnaire was completed by the 35 primary and post-primary teachers who will deliver the intervention. Results are analysed in terms of how teachers’ responses compare with their pupil attitudes by considering their confidence in tackling sectarian issues in the classroom and how their previous experience and training relate to their hopes and concerns for the intervention.


Expected Outcomes

Results from the young people’s survey are discussed in the light of the role of social identity dimensions and their relationship to sectarian attitudes and reported bystander behaviour in sectarian school incidents. Furthermore, results related to pupils’ sectarian attitudes will be compared with teachers’ reported confidence in tackling sectarianism in the classroom. The teacher questionnaire also presents interesting findings in relation to teachers’ previous training and experience and how this may influence different perspectives on peace and reconciliation interventions and their expectations of what these could achieve. The paper concludes with potential implications for peace education initiatives and related teacher training in Northern Ireland and beyond. The implications will be of particular interest to policy makers, educators and those working in the area of peace education to design and implement interventions.


References

Bogardus, E. S. (1947) Measurement of Personal-Group Relations. Sociometry, 10: 4: 306–311. Hughes, J., Donnelly, C., Hewstone, M., Gallagher, T. & Carlisle, K. (2010) School partnerships and reconciliation: An evaluation of school collaboration in Northern Ireland. Belfast: Queen’s University Belfast. Available online: http://www.schoolsworkingtogether.com/documents/School%20collaboration%20in%20NI%202010.pdf. (accessed 27th Jan 2010) Palmer, S. & Cameron, L. (2011, May). What are the moderators and mediators of children’s bystander behaviour in the context of intergroup discrimination? Paper session presented at the UNA Global Biennial Conference 2011: Building Peaceable Communities: The Power of Early Childhood, Amsterdam, Holland. Phinney, J. S. (1992). The Multigroup Ethnic Identity Measure: A new scale for use with diverse groups. Journal of Adolescent Research, 7, 156–176.

The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Power and Energy Implications of the Number of Threads Used on the Intel Xeon Phi

Energy consumption has become an important area of research of late. With the advent of new manycore processors, situations have arisen where not all the processors need to be active to reach an optimal relation between performance and energy usage. In this paper a study of the power and energy usage of a series of benchmarks, the PARSEC and the SPLASH- 2X Benchmark Suites, on the Intel Xeon Phi for different threads configurations, is presented. To carry out this study, a tool was designed to monitor and record the power usage in real time during execution time and afterwards to compare the r

Paving the way to nanoionics: atomic origin of barriers for ionic transport through interfaces

The blocking of ion transport at interfaces strongly limits the performance of electrochemical nanodevices for energy applications. The barrier is believed to arise from space-charge regions generated by mobile ions by analogy to semiconductor junctions. Here we show that something different is at play by studying ion transport in a bicrystal of yttria (9% mol) stabilized zirconia (YSZ), an emblematic oxide ion conductor. Aberration-corrected scanning transmission electron microscopy (STEM) provides structure and composition at atomic resolution, with the sensitivity to directly reveal the oxygen ion profile. We find that Y segregates to the grain boundary at Zr sites, together with a depletion of oxygen that is confined to a small length scale of around 0.5 nm. Contrary to the main thesis of the space-charge model, there exists no evidence of a long-range O vacancy depletion layer. Combining ion transport measurements across a single grain boundary by nanoscale electrochemical strain microscopy (ESM), broadband dielectric spectroscopy measurements, and density functional calculations, we show that grain-boundary-induced electronic states act as acceptors, resulting in a negatively charged core. Ultimately, it is this negative charge which gives rise to the barrier for ion transport at the grain boundary

Assessment of cataract surgical outcomes in settings where follow-up is poor:PRECOG, a multicentre observational study

Background: Poor follow-up after cataract surgery in developing countries makes assessment of operative quality uncertain. We aimed to assess two strategies to measure visual outcome: recording the visual acuity of all patients 3 or fewer days postoperatively (early postoperative assessment), and recording that of only those patients who returned for the final follow-up examination after 40 or more days without additional prompting. Methods: Each of 40 centres in ten countries in Asia, Africa, and Latin America recruited 40-120 consecutive surgical cataract patients. Operative-eye best-corrected visual acuity and uncorrected visual acuity were recorded before surgery, 3 or fewer days postoperatively, and 40 or more days postoperatively. Clinics logged whether each patient had returned for the final follow-up examination without additional prompting, had to be actively encouraged to return, or had to be examined at home. Visual outcome for each centre was defined as the proportion of patients with uncorrected visual acuity of 6/18 or better minus the proportion with uncorrected visual acuity of 6/60 or worse, and was calculated for each participating hospital with results from the early assessment of all patients and the late assessment of only those returning unprompted, with results from the final follow-up assessment for all patients used as the standard. Findings: Of 3708 participants, 3441 (93%) had final follow-up vision data recorded 40 or more days after surgery, 1831 of whom (51% of the 3581 total participants for whom mode of follow-up was recorded) had returned to the clinic without additional prompting. Visual outcome by hospital from early postoperative and final follow-up assessment for all patients were highly correlated (Spearman's r_s=0·74, p<0·0001). Visual outcome from final follow-up assessment for all patients and for only those who returned without additional prompting were also highly correlated (r_s=0·86, p<0·0001), even for the 17 hospitals with unprompted return rates of less than 50% (r_s=0·71, p=0·002). When we divided hospitals into top 25%, middle 50%, and bottom 25% by visual outcome, classification based on final follow-up assessment for all patients was the same as that based on early postoperative assessment for 27 (68%) of 40 centres, and the same as that based on data from patients who returned without additional prompting in 31 (84%) of 37 centres. Use of glasses to optimise vision at the time of the early and late examinations did not further improve the correlations. Interpretation: Early vision assessment for all patients and follow-up assessment only for patients who return to the clinic without prompting are valid measures of operative quality in settings where follow-up is poor. Funding: ORBIS International, Fred Hollows Foundation, Helen Keller International, International Association for the Prevention of Blindness Latin American Office, Aravind Eye Care System. © 2013 Congdon et al. Open Access article distributed under the terms of CC BY.

Schizophrenia risk from complex variation of complement component 4

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.