A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B+T-NK-X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8+ T cells and increased over time. Only the revertant CD8+T cells showed normal expression of CD132 and the various CD8+T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ+T cells and differentiated CD4+CD27-effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8+T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells

Spatial variability in sustainable development trajectories in South Africa:provincial level safe and just operating spaces

The Sustainable Development Goals (SDGs) represents the first globally agreed framework to address human development and environmental stewardship in an integrated way. One approach to summarising national SDG status is our “barometer for inclusive sustainable development in South Africa”. The barometer downscales global social and planetary boundaries to provide status and trends for 20 critical indicators of environmental stress and social deprivation. In this paper, we explore the sub-national heterogeneity in sustainable development indicators by creating barometers defining the ‘safe and just operating space’ for South Africa’s nine provinces. Our results show that environmental stress varies significantly and provinces need to focus on quite different issues. Although generally environmental stress is increasing, there are areas where it is decreasing, most notably, marine harvesting. Social deprivation results show more of a pattern with high levels of deprivation in employment, income and safety across the provinces, and historically disadvantaged provinces showing the most deprivation overall. Although deprivation is generally decreasing, there are notable exceptions such as food security in six provinces. Our provincial barometers and trend plots are novel in that they present comparable environmental and social data on key indicators over time for all South Africa’s provinces. They are visual tools that communicate the range of key challenges and risks that provincial governments face, and are non-specialist and accessible to a range of audiences. In addition, the paper provides a critical case study of spatial disaggregation of national data that is required for the SDGs implementation

A pragmatic approach to evaluate alternative indicators to GDP

The serious economic crisis broken out in 2008 highly stressed the limitations of GDP used as a well-being indicator and as a predictive tool for economy. This induced the need to identify new indicators able to link the economic prosperity of a country to aspects of sustainable development and externalities, both positive and negative, in the long run. The aim of this paper is to introduce a structured approach which supports the choice or the construction of alternative indicators to GDP. The starting point is the definition of what a well-being indicator actually should represent according to the Recommendations of the Stiglitz-Sen-Fitoussi Report on the measurement of economic performance and social progress. Then the paper introduces a systematic procedure for the analysis of well-being indicators. The different phases of this procedure entail the checking of indicators technical properties and their effect on the representational efficacy. Finally, some of the most representative well-being indicators drawn from the literature are compared and a detailed application example is propose

The Arabidopsis RNA Polymerase II Carboxyl Terminal Domain (CTD) Phosphatase-Like1 (CPL1) is a biotic stress susceptibility gene

© 2018, The Author(s). Crop breeding for improved disease resistance may be achieved through the manipulation of host susceptibility genes. Previously we identified multiple Arabidopsis mutants known as enhanced stress response1 (esr1) that have defects in a KH-domain RNA-binding protein and conferred increased resistance to the root fungal pathogen Fusarium oxysporum. Here, screening the same mutagenized population we discovered two further enhanced stress response mutants that also conferred enhanced resistance to F. oxysporum. These mutants also have enhanced resistance to a leaf fungal pathogen (Alternaria brassicicola) and an aphid pest (Myzus persicae), but not to the bacterial leaf pathogen Pseudomonas syringae. The causal alleles in these mutants were found to have defects in the ESR1 interacting protein partner RNA Polymerase II Carboxyl Terminal Domain (CTD) Phosphatase-Like1 (CPL1) and subsequently given the allele symbols cpl1-7 and cpl1-8. These results define a new role for CPL1 as a pathogen and pest susceptibility gene. Global transcriptome analysis and oxidative stress assays showed these cpl1 mutants have increased tolerance to oxidative stress. In particular, components of biotic stress responsive pathways were enriched in cpl1 over wild-type up-regulated gene expression datasets including genes related to defence, heat shock proteins and oxidative stress/redox state processes

In search of income reference points for SLCA using a country level sustainability benchmark (part 1): fair inequality. A contribution to the Oiconomy project

Purpose: This paper is part 1 of our twin articles on income reference points for Social Life Cycle Assessment (SLCA). Preventative costs based LCA systems, such as the EcoCost system and the Oiconomy system, need targets (performance reference points) to determine the marginal preventative costs, the costs of the most expensive measure that globally needs to be employed to reach the target. To extend the EcoCost system for social issues, targets are required for issues like fair wages and fair inequality of wages, issues for which no agreed standard, no effect level or target exists. One way of setting targets is to take best practices as benchmark, e.g. the practices of a group of best performing countries. The purpose of this part 1 article is to first develop a well-founded benchmark group of the 20 % best performing countries and thereafter propose a well-founded target for the issue of inequality for preventative costs based SLCA, which can also serve as performance reference point for SLCA in general and for other uses. In part 2, for the same purposes and using the same benchmark group, we propose targets for fair minimum wages for every country. Methods: A benchmark group of countries for the setting of targets was determined by an assessment of available country performance indicators, based on 5 criteria. Thereafter, we derived a proposal for a maximum inequality ratio based on existing democratically determined inequality ratios in the benchmark group. Results and discussion: The Sustainable Society Index–Human Wellbeing proved the best indicator for a country benchmark for preventative cost-based SLCA. Using the average of maximum democratically determined income differences in a benchmark group of countries determined by this index, a performance reference point for SLCA for the issue of fair inequality was derived and proposed, resulting in a maximum ratio of income differences for governmental institutions of 14.1, for government ruled companies of 18.3 and for industry of a factor 23.8. Conclusions: It proved possible to derive a target for maximum inequality of wages, based on democratic choices in a benchmark group of the 20 % best performing countries. The target for governmental institutions may be called objective, and proposed augmentations for government ruled companies and industry, though value choices, seem reasonable for the consumer who requires prevention of all possible harm as consequence of his purchase choices and who, as a voter, contributes to governmental standards

Evaluatie ontwerp havendammen Hoek van Holland

Deze studie bestaat uit een vooronderzoek, gevolgd door drie deelonderzoeken. Vooronderzoek (deel I): Van de Noorder- en Zuiderhavendam te Hoek van Holland wordt nagegaan wat de ontwerp- en uitvoeringsfilosofie geweest is. Dit onderzoek richt zich met name on: 1 - de ontwikkeling van het dwarsprofiel. 2 - de dimensionering van de bekledingslaag van betonkubussen. Deelonderzoeken (deel II, III en IV): II Schade-analyse: Teneinde tot een uitspraak te komen over de feitelijke stabiliteit van de gebouwde dammen wordt onderzocht: - of er schade aan de dammen is opgetreden en of deze gerelateerd is aan opgetreden stormen. - welke schademechanismen ten grondslag kunnen liggen aan een eventueel falen yan de dammen (foutenboom). - of de ontwerprandvoorwaarden aanleiding geven tot een reëele schadeverwachting. - of andere benaderingen tot meer inzicht in de stabiliteit leiden. III Toetsing kruinhoogten: Eén der belangrijkste ontwerpvariabelen: de kruinhoogte van de dammen, wordt getoetst aan de functies die de dammen vervullen. Deze variabele bepaalt in belangrijke mate de kosten van de dammen. IV Meten aan de dammen: Om effectief onderhoud te kunnen plegen moet schade waargenomen worden. De mogelijkheden en beperkingen van verschillende meetprincipes worden onderzocht teneinde een geschikt meetprogramma voor de dammen te verkrijgen.Hydraulic EngineeringCivil Engineering and Geoscience

Habitat type and schooling interactively determine refuge-seeking behavior in a coral reef fish throughout ontogeny

Habitat selection by coral reef fish is influenced by a variety of biological and abiotic factors, but the relative importance of these factors is expected to change throughout ontogeny, especially for species that utilize different habitats during their life cycle. In this study, 2 in situ choice experiments were designed to test the individual as well as the interactive effects of habitat structure and schooling (with conspecifics or heterospecifics) on refuge-seeking behavior of a coral reef fish. The experiments were conducted for 3 size-classes of the common reef fish Haemulon flavolineatum, a species that shows multiple habitat shifts throughout its ontogeny. We tested the hypothesis that, due to the additive effects of schooling and structure in providing suitable refuge, fish would be more attracted to a microhabitat with conspecifics or heterospecifics than to a microhabitat or conspecifics alone. In the habitat-only experiment, early juveniles (<3 cm fork length) showed no preference for any microhabitat structures, whereas larger fish preferred complex mangrove structure to seagrass, rubble, or coral. In the second experiment, which offered various combinations of habitat, including habitat with both conspecifics and heterospecifics, the preference for mangrove structure was completely replaced by attraction to conspecifics for all size-classes. Unexpectedly, the combination of conspecifics and habitat structure showed no additive effect. The results demonstrate that although H. flavolineatum makes multiple shifts in habitat throughout its life cycle, in the absence of other biological or environmental drivers preference for shelter habitat past the early post-settlement stage remains the same. The study further demonstrates the critical role of the presence of conspecifics in microhabitat choice, and provides a better understanding of the relative importance of these factors, whether in isolation or additively, in selection of refuge habitat by a reef fish. © Inter-Research 2011.Chantal M. Huijbers, Ivan Nagelkerken, Laura L. Govers, Madelon van de Kerk, Jeffrey J. Oldenburger and Jan H.F. de Brouwe