Positive and negative roles of the trans-acting T cell factor-1 for the acquisition of distinct Ly-49 MHC class I receptors by NK cells.

Members of the Ly-49 gene family code for class I MHC-specific receptors that regulate NK cell function. Due to a combinatorial distribution of Ly-49 receptors, NK cells display considerable clonal heterogeneity. The acquisition of one Ly-49 receptor, Ly-49A is strictly dependent on the transcriptional trans-acting factor T cell-specific factor-1 (TCF-1). Indeed, TCF-1 binds to two sites in the Ly-49a promoter and regulates its activity, suggesting that the Ly-49a gene is a direct TCF-1 target. TCF-1 deficiency resulted in the altered usage of additional Ly-49 receptors. We show in this study, using TCF-1 beta(2)-microglobulin double-deficient mice, that these repertoire alterations are not due to Ly-49/MHC class I interactions. Our findings rather suggest a TCF-1-dependent, cell autonomous effect on the acquisition of multiple Ly-49 receptors. Besides reduced receptor usage (Ly-49A and D), we also observed no effect (Ly-49C) and significantly expanded (Ly-49G and I) receptor usage in the absence of TCF-1. These effects did not in all cases correlate with the presence of TCF binding sites in the respective proximal promoter. Therefore, besides TCF-1 binding to the proximal promoter, Ly-49 acquisition may also be regulated by TCF-1 binding to more distant cis-acting elements and/or by regulating the expression of additional trans-acting factors. Consistent with the observed differential, positive or negative role of TCF-1 for Ly-49 receptor acquisition, reporter gene assays revealed the presence of an inducing as well as a repressing TCF site in certain proximal Ly-49 promoters. These findings reveal an important role of TCF-1 for the formation of the NK cell receptor repertoire.

Improvement of the HIV/AIDS vaccine candidate NYVAC-C by deletion of the viral type I IFN inhibitor and/or acquisition of replication competence

Background: Recombinant viruses based on the attenuated vaccinia virus strain NYVAC are promising HIV vaccine candidates as phase I/II clinical trials have shown good safety and immunogenicity profiles. However, this NYVAC strain is non-replicating in most human cell lines and encodes viral inhibitors of the immune system. Methods: With the aim to increase the immune potency of the current NYVAC-C vector (expressing the codon optimized clade C HIV-1 genes encoding gp120 and Gag-Pol-Nef polyprotein), we have generated and characterized three NYVAC-C-based vectors by, 1) deletion of the viral type I IFN inhibitor gene (NYVAC-CdeltaB19R), 2) restoration of virus replication competence in human cells by re-inserting K1L and C7L host range genes (NYVAC-C-KC) and, 3) combination of both strategies (NYVACC- KC-deltaB19R). Results: Insertion of the KC fragment restored the replication competence of the viruses in human cells (HeLa cells and primary dermal fibroblasts and keratinocytes), increased the expression of HIV antigens by more than 3-fold compared to the non-replicating homologs, inhibited apoptosis induced by the parental NYVAC-C and retained attenuation in a newborn mouse model. In adult mice, replication-competent viruses showed a limited capacity to replicate in tissues surrounding the inoculation site (ovaries and lymph nodes). After infection of keratinocytes, PBMCs and dendritic cells these viruses induced differential modulation in specific host cell signal transduction pathways, triggering genes important in immune modulation. Conclusion: We have developed improved NYVAC-C-based vectors with enhanced HIV-1 antigen expression, with the ability to replicate in cultured human cells and partially in some tissues, with an induced expression of cellular genes relevant to immune system activation, and which trigger IFN-dependent and independent signalling pathways, while maintaining a safety phenotype. These new vectors are promising new HIV vaccine candidates. These studies were performed within the Poxvirus Tcell Vaccine Discovery Consortium (PTVDC) which is part of the CAVD program.

Pre-mRNA trans-splicing: from kinetoplastids to mammals, an easy language for life diversity

Since the discovery that genes are split into intron and exons, the studies of the mechanisms involved in splicing pointed to presence of consensus signals in an attempt to generalize the process for all living cells. However, as discussed in the present review, splicing is a theme full of variations. The trans-splicing of pre-mRNAs, the joining of exons from distinct transcripts, is one of these variations with broad distribution in the phylogenetic tree. The biological meaning of this phenomenon is discussed encompassing reactions resembling a possible noise to mechanisms of gene expression regulation. All of them however, can contribute to the generation of life diversity.

20 Year Strategy for the Irish Language 2010 to 2030 Progress Report: 2010 - 2015

Over the last five years, the Department of Education and Skills (DES) has continued to fulfil the commitments set out in its implementation plan under the 20-Year Strategy for Irish on a phased and systematic basis. This report gives an insight into the progress made during this period under the following headings: Interdepartmental High-Level Group Gaeltacht education Curriculum development O Primary level O Post-primary level Assessment COGG - Support services and resources Teacher education Links with the use of the language outside of school O Irish language colleges Exemptions from Irish Provision for Irish-medium schools Policy for Irish in the public service.

20 Year Strategy for the Irish Language 2010 to 2030 Progress Report: July 2013 - Sept 2014

DES has commenced a review of education in the Gaeltacht with a view to identifying options for educational provision in primary and post-primary schools in Gaeltacht areas of varying linguistic profiles as well as clarifying the Department’s policy with regard to teaching through Irish in such schools. The review will also look at the impact of pre-school provision on primary education in Gaeltacht areas. Furthermore, the review will identify support measures for teachers’ practice that would be required to improve teaching through Irish in Gaeltacht schools. This review will complement the implementation of the Gaeltacht Act 2012.

20 Year Strategy for the Irish Language 2010-2030

The objective of Government policy in relation to Irish is to increase on an incremental basis the use and knowledge of Irish as a community language. Specifically, the Government’s aim is to ensure that as many citizens as possible are bilingual in both Irish and English. It is an integral component of the Government’s Irish language policy that close attention be given to its place in the Gaeltacht, particularly in light of research which indicates that the language’s viability as a household and community language in the Gaeltacht is under threat. The aim of Government policy is also to: increase the number of families throughout the country who use Irish as the daily language of communication; provide linguistic support for the Gaeltacht as an Irish-speaking community and to recognise the issues which arise in areas where Irish is the household and community language; ensure that in public discourse and in public services the use of Irish or English will be, as far as practical, a choice for the citizen to make and that over time more and more people throughout the State will choose to do their business in Irish; and ensure that Irish becomes more visible in our society, both as a spoken language by our citizens and also in areas such as signage and literature

Development of a National English Language Policy and Framework for Legally Resident Adult Immigrants - Horwath Report

The Office of the Minister for Integration (OMI), in conjunction with the Department of Education and Science (DES), commissioned an independent review to assist in the development of a national English Language policy and framework for legally-resident adult immigrants. Horwath Consulting Ireland, in association with Rambll Management and Matrix Knowledge Group, were awarded the contract to undertake this assignment. The terms of reference for the assignment state that: “proposed future developments will be governed by a clear strategy which reflects the importance of English language tuition in overall integration objectives and which addresses key coordination, technical, funding and service-delivery issues."

Speech, language and communication therapy action plan

This is the first update newsletter of the Speech, language and communication therapy action plan. The action plan was developed by the Department of Health, Social Services and Public Safety (DHSSPS) with the aim that all children and young people at risk of or presenting with speech, language or communication needs will be able to benefit from timely support and integrated services that best meet their requirements.The Public Health Agency (PHA), in partnership with the Health and Social Care Board (HSCB), has been tasked with implementing the action plan.The update includes news on the publication of the Healthy child, health future framework and highlights other points of progress so far, including the development of the Family Support NI website. There is also an invite for parents to join a focus group to influence and assist with the implementation of the action plan.�

Healthy child, healthy future - Speech and language therapy: Factsheet for parents 3. Talk to your child in your own language

This factsheet encourages non-English speaking parents to talk to their children in their own language.

Healthy child, healthy future: speech and language therapy for children

This resource is designed to reinforce a collaborative approach between speech and language therapists, referrers and parents in the identification and management of children with developmental speech and language and communication needs (including children with feeding and/or swallowing difficulties).

Healthy child, health future - Speech and language therapy: Factsheet for parents 2. Helping your young non-fluent child

This factsheet outlines how parents can help their child speak more fluently, without stammering.

Healthy child, healthy future - Speech and language therapy: Factsheet for parents 6. Tips for talking: children aged 4 to 5 years

This factsheet highlights simple ideas to encourage speech in children around 4 to 5 years old.

Healthy child, healthy future - Speech and language therapy aide memoire for health visitors

This card outlines the key skills, causes for concern and management options for children aged 24 months and 30 months.

Healthy child, healthy future - Speech and language therapy: Factsheet for parents 1. Does my child speak clearly?

This factsheet describes how parents can help their child speak more clearly.

Healthy child, healthy future - Speech and language therapy: Factsheet for parents 5. Does my child have a voice problem?

This factsheet describes voice disorders such as 'hoarseness' in children and what parents can do to help their child with a voice problem.