Highly diverse TCRα chain repertoire of pre-immune CD8(+) T cells reveals new insights in gene recombination.

Although the T-cell receptor αδ (TCRαδ) locus harbours large libraries of variable (TRAV) and junctional (TRAJ) gene segments, according to previous studies the TCRα chain repertoire is of limited diversity due to restrictions imposed by sequential coordinate TRAV-TRAJ recombinations. By sequencing tens of millions of TCRα chain transcripts from naive mouse CD8(+) T cells, we observed a hugely diverse repertoire, comprising nearly all possible TRAV-TRAJ combinations. Our findings are not compatible with sequential coordinate gene recombination, but rather with a model in which contraction and DNA looping in the TCRαδ locus provide equal access to TRAV and TRAJ gene segments, similarly to that demonstrated for IgH gene recombination. Generation of the observed highly diverse TCRα chain repertoire necessitates deletion of failed attempts by thymic-positive selection and is essential for the formation of highly diverse TCRαβ repertoires, capable of providing good protective immunity.

PHA/HSCB Hidden Harm Action Plan

This joint PHA/HSCB Hidden Harm Action Plan - Responding to the needs of children born to and living with parental alcohol and drug misuse in Northern Ireland, has been prepared for the DHSSPS in response to the PfA target on Hidden Harm. The plan was approved by DHSSPS in October 2009.

Playing Second Fiddle: Expert Advice and Decision-Making in Switzerland

This thesis concerns the role of scientific expertise in the decision-making process at the Swiss federal level of government. It aims to understand how institutional and issue-specific factors influence three things: the distribution of access to scientific expertise, its valuation by participants in policy for- mulation, and the consequence(s) its mobilization has on policy politics and design. The theoretical framework developed builds on the assumption that scientific expertise is a strategic resource. In order to effectively mobilize this resource, actors require financial and organizational resources, as well as the conviction that it can advance their instrumental interests within a particular action situation. Institutions of the political system allocate these financial and organizational resources, influence the supply of scientific expertise, and help shape the venue of its deployment. Issue structures, in turn, condition both interaction configurations and the way in which these are anticipated by actors. This affects the perceived utility of expertise mobilization, mediating its consequences. The findings of this study show that the ability to access and control scientific expertise is strongly concentrated in the hands of the federal administration. Civil society actors have weak capacities to mobilize it, and the autonomy of institutionalized advisory bodies is limited. Moreover, the production of scientific expertise is undergoing a process of professionalization which strengthens the position of the federal administration as the (main) mandating agent. Despite increased political polarization and less inclu- sive decision-making, scientific expertise remains anchored in the policy subsystem, rather than being used to legitimate policy through appeals to the wider population. Finally, the structure of a policy problem matters both for expertise mobilization and for the latter's impact on the policy process, be- cause it conditions conflict structures and their anticipation. Structured problems result in a greater overlap between the principal of expertise mobilization and its intended audience, thereby increasing the chance that expertise shapes policy design. Conversely, less structured problems, especially those that involve conflicts about values and goals, reduce the impact of expertise.

Strategic development review of health board food control laboratories

The Official Food Safety laboratories have a critical role in ensuring food safety and public health for the whole population of the Republic of Ireland. These public health laboratories are made up of 7 microbiological testing laboratories and 3 chemical or Public Analyst’s laboratories. The laboratories are regionally based and offer an accredited (INAB) service to 10 health boards thus spanning the country. The role of the laboratories is to test food for compliance with the relevant legislation and guidelines, identify food-borne hazards and disease outbreaks, provide essential risk assessment information for national and international needs, provide a food testing service for consumers and a water testing service on a national basis. They also participate in dedicated National and EU surveys under the auspices of the Food Safety Authority of Ireland (FSAI). There has been significant investment and development in food-related public health protection in Ireland in recent years. However, there are still a number of issues that have the potential to impact on these laboratories in delivering a fully effective public health service in a cost efficient manner. Building on what has been achieved to date, this strategic review identifies those issues to be addressed in order to ensure (1) a cost effective national co-ordinated food safety laboratory service, (2) that future laboratory service needs are accounted for in the delivery of their Public Health role, and (3) that this Service meets both national and international requirements and standards.

Tackling Health Inequalities through Action on the Social Determinants of Health: Lessons from Experience

Briefing 10 - Lessons from experience This document, commissioned by Public Health England, and written by the UCL Institute of Health Equity, sets out 12 points to consider when taking action locally on the social determinants of health. It is intended as a source of information on approaches to consider when devising local programmes and strategies to reduce health inequalities. It complements the other briefings and evidence reviews in this series, which provide more detail on action on specific social determinant areas, such as employment and early years interventions, including information on impacts and cost effectiveness where available. The 12 steps are divided across three parts. The first part sets out four strategies that help prioritise action on health equity. The next steps are principles of effective action on the social determinants of the health, presented in the second part. Finally, the steps in part three outline ways of ensuring that measures to increase health equity are sustainable and have impact over the long term. The briefing is available to download above. This document is part of a series. An overview document which provides an introduction to this and other documents in the series, and links to the other topic areas, is available on the ‘Local Action on health inequalities’ project page. A video of Michael Marmot introducing the work is also available on our videos page.

Enough is Enough - Food Poverty Scoping Exercise

In March 2015, over 80 people, representing food banks, churches, advice services, community organisations, statutory agencies and universities attended the ‘Enough is Enough’  launch event in City Church, Belfast to examine the rising demand for emergency food across the city.The ‘Enough is Enough’ project aims to harness the expertise of health and social care professionals, city councillors, advice workers, food banks, community and faith based organisations and strategic bodies across Belfast to collectively address the issue of food poverty. This scoping study lays the foundation for developing an action plan to tackle food poverty in Belfast in collaboration with the community, voluntary and statutory sectors.The Belfast Food Network (BFN) commissioned the project with funding from the Public Health Agency. The research was carried out by Jenny McCurry, who also wrote the report, on behalf of Advice NI.  The project was initiated and developed by Dr Elizabeth Mitchell, Institute of Public Health in Ireland, in her role as convener of the BFN Food Poverty Working Group (BFN/FPWG). Thanks are due to Kevin Higgins, Head of Policy, Advice NI, and Kerry Melville, Co-ordinator, BFN, for their involvement in the project.The BFN is a founding member of the pioneering Sustainable Food Cities Network (SFC). Therapidly growing BFN was established in March 2014 to work with partners to establish a successful Sustainable Food City in Belfast.ACCESS AUDIO AND VIDEO FROM THE EVENT

Action plan against Drugs and Drug Addiction: Horizons 2008

Portugese action plan against drugs.This resource was contributed by The National Documentation Centre on Drug Use.

Report Against Drugs- an action plan to combat substance abuse in Longford.

The Forum for Longford was started in 1997 to provide a co-ordinated inter-agency approach to identify and help tackle social problems in Longford. A survey was carried out with 1,331 post-primary students to ascertain attitudes and behaviours towards alcohol, smoking and drug use. Of the pupils interviewed, 64% had taken an alcoholic drink at age 15 or younger; of these 73% had their first drink between the ages of 12 to 15. Of those that had experience of alcohol, 51% drank several times a week or daily. For smoking, 67% had smoked a cigarette; of these 8% smoked 5 or more daily. Of those that smoked, 47% began between the ages of 11 to 14. With regard to illegal drugs 27% had used cannabis, 20% had used inhalants, 10% hallucinogens, 9% amphetamines and 7.4% had used ecstasy. Following on form these findings, the report makes several recommendations, including the formation of a community task force, Garda/ neighbourhood watch response, schools prevention and information. Also among these key areas are the role of parents, the needs of young people and facilities for young people.This resource was contributed by The National Documentation Centre on Drug Use.

The Quorum-Sensing Molecules Farnesol/Homoserine Lactone and Dodecanol Operate via Distinct Modes of Action in Candida albicans.

Living as a commensal, Candida albicans must adapt and respond to environmental cues generated by the mammalian host and by microbes comprising the natural flora. These signals have opposing effects on C. albicans, with host cues promoting the yeast-to-hyphal transition and bacteria-derived quorum-sensing molecules inhibiting hyphal development. Hyphal development is regulated through modulation of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and it has been postulated that quorum-sensing molecules can affect filamentation by inhibiting the cAMP pathway. Here, we show that both farnesol and 3-oxo-C(12)-homoserine lactone, a quorum-sensing molecule secreted by Pseudomonas aeruginosa, block hyphal development by affecting cAMP signaling; they both directly inhibited the activity of the Candida adenylyl cyclase, Cyr1p. In contrast, the 12-carbon alcohol dodecanol appeared to modulate hyphal development and the cAMP signaling pathway without directly affecting the activity of Cyr1p. Instead, we show that dodecanol exerted its effects through a mechanism involving the C. albicans hyphal repressor, Sfl1p. Deletion of SFL1 did not affect the response to farnesol but did interfere with the response to dodecanol. Therefore, quorum sensing in C. albicans is mediated via multiple mechanisms of action. Interestingly, our experiments raise the possibility that the Burkholderia cenocepacia diffusible signal factor, BDSF, also mediates its effects via Sfl1p, suggesting that dodecanol's mode of action, but not farnesol or 3-oxo-C(12)-homoserine lactone, may be used by other quorum-sensing molecules.

Les stratégies politiques et foncières des grands propriétaires fonciers en action : études de cas

Ce cahier présente une analyse comparée de quatre études de cas menées au sein du projet consacré aux stratégies politiques et foncières des grands propriétaires fonciers suisses à l'IDHEAP en 2007-2008. Ces études de cas concernent le complexe immobilier de « La Maladière » à Neuchâtel, le pôle de développement économique du Wankdorf à Berne, le « Centre Boujean » à Bienne ainsi que la place d'armes de Thoune. De chacun de ces cas sont présentés la chronologie des événements, les étapes et régimes du projet, les configurations et stratégies des acteurs, les impacts sur la durabilité ainsi qu'une discussion des résultats à la lumière des hypothèses du projet. L'analyse comparée fait le point des configurations et stratégies des acteurs qui sont ensuite mises en relation avec les régimes institutionnels et la durabilité des usages du sol. L'un des messages principaux est que, aujourd'hui, on ne peut plus séparer l'aménagement du territoire du foncier si l'on veut atteindre les objectifs politiques du développement du territoire. Die vorliegende Publikation enthält eine vergleichende Analyse von vier Fallstudien, die im Rahmen des Projektes zu den Strategien der grossen Grundeigentümer der Schweiz im Bereich der Ausübung ihrer Eigentumsrechte und ihrer Interventionen auf der Ebene der Raumplanung durchgeführt wurden. Sie betreffen den Immobilienkomplex ,,La Maladière" in Neuenburg, den Entwicklungsschwerpunkt Wankdorf in Bern, das ,,Centre Boujean" in Biel und den Waffenplatz Thun. Die Zusammenfassungen der Fallstudien enthalten Angaben zur Chronologie der Ereignisse, zu den verschiedenen Etappen der Projektentwicklung und der entsprechenden Regime, zu den Akteurkonfigurationen und -strategien, zu den Auswirkungen der Projekte auf die nachhaltige Entwicklung sowie eine Diskussion der empirischen Befunde im Lichte der Projekthypothesen. Die vergleichende Analyse nimmt eine Typologie der Akteurkonfigurationen vor und diskutiert deren Folgen für die institutionellen Regime und für die nachhaltige Entwicklung der Ressource Boden. Eines der Hauptergebnisse liegt in der Feststellung, dass sich heute Raumplanung mehr den je mit den Bodeneigentumsverhältnissen befassen muss, um die beabsichtigten politischen Entwicklungsziele zu erreichen.

Light receptor action is critical for maintaining plant biomass at warm ambient temperatures.

The ability to withstand environmental temperature variation is essential for plant survival. Former studies in Arabidopsis revealed that light signalling pathways had a potentially unique role in shielding plant growth and development from seasonal and daily fluctuations in temperature. In this paper we describe the molecular circuitry through which the light receptors cry1 and phyB buffer the impact of warm ambient temperatures. We show that the light signalling component HFR1 acts to minimise the potentially devastating effects of elevated temperature on plant physiology. Light is known to stabilise levels of HFR1 protein by suppressing proteasome-mediated destruction of HFR1. We demonstrate that light-dependent accumulation and activity of HFR1 are highly temperature dependent. The increased potency of HFR1 at warmer temperatures provides an important restraint on PIF4 that drives elongation growth. We show that warm ambient temperatures promote the accumulation of phosphorylated PIF4. However, repression of PIF4 activity by phyB and cry1 (via HFR1) is critical for controlling growth and maintaining physiology as temperatures rise. Loss of this light-mediated restraint has severe consequences for adult plants which have greatly reduced biomass.

Alcohol Action Ireland's conference - presentations.

Session One - Alcohol and Crime in Ireland, Counting the Costs• National Quantitative Research, Director of Alcohol Action Ireland, Fiona Ryan• National and International Context - Dr. Anne Hope• Economic Costs of Alcohol Related Crime - Senior Lecturer, Sean Byrne Session Two - Exploring Responses to Alcohol and Crime• Garda Juvenile Diversion Program - Superintendent, Colette Quinn• HSE South - Health Promotion Officer, Sandra Coughlan Session Three - Hidden Harm - Sexual and Domestic Violence and Alcohol• Rape Crisis Network Ireland - Cliona Saidlear• SAFE Ireland - Director, Sharon O’ Halloran• Alcohol Concern - Director, Christine Toft• Men Overcoming Violence (MOVE) - CEO, Thomas Bibby• Head of Crime Reduction Branch, Martine Mc Killop & Belfast Community Safety Partnership, Stevie LaveryThis resource was contributed by The National Documentation Centre on Drug Use.

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

The modern approach to the development of new chemical entities against complex diseases, especially the neglected endemic diseases such as tuberculosis and malaria, is based on the use of defined molecular targets. Among the advantages, this approach allows (i) the search and identification of lead compounds with defined molecular mechanisms against a defined target (e.g. enzymes from defined pathways), (ii) the analysis of a great number of compounds with a favorable cost/benefit ratio, (iii) the development even in the initial stages of compounds with selective toxicity (the fundamental principle of chemotherapy), (iv) the evaluation of plant extracts as well as of pure substances. The current use of such technology, unfortunately, is concentrated in developed countries, especially in the big pharma. This fact contributes in a significant way to hamper the development of innovative new compounds to treat neglected diseases. The large biodiversity within the territory of Brazil puts the country in a strategic position to develop the rational and sustained exploration of new metabolites of therapeutic value. The extension of the country covers a wide range of climates, soil types, and altitudes, providing a unique set of selective pressures for the adaptation of plant life in these scenarios. Chemical diversity is also driven by these forces, in an attempt to best fit the plant communities to the particular abiotic stresses, fauna, and microbes that co-exist with them. Certain areas of vegetation (Amazonian Forest, Atlantic Forest, Araucaria Forest, Cerrado-Brazilian Savanna, and Caatinga) are rich in species and types of environments to be used to search for natural compounds active against tuberculosis, malaria, and chronic-degenerative diseases. The present review describes some strategies to search for natural compounds, whose choice can be based on ethnobotanical and chemotaxonomical studies, and screen for their ability to bind to immobilized drug targets and to inhibit their activities. Molecular cloning, gene knockout, protein expression and purification, N-terminal sequencing, and mass spectrometry are the methods of choice to provide homogeneous drug targets for immobilization by optimized chemical reactions. Plant extract preparations, fractionation of promising plant extracts, propagation protocols and definition of in planta studies to maximize product yield of plant species producing active compounds have to be performed to provide a continuing supply of bioactive materials. Chemical characterization of natural compounds, determination of mode of action by kinetics and other spectroscopic methods (MS, X-ray, NMR), as well as in vitro and in vivo biological assays, chemical derivatization, and structure-activity relationships have to be carried out to provide a thorough knowledge on which to base the search for natural compounds or their derivatives with biological activity.