A moonlighting metabolic protein influences repair at DNA double-stranded breaks.

Catalytically active proteins with divergent dual functions are often described as 'moonlighting'. In this work we characterize a new, chromatin-based function of Lys20, a moonlighting protein that is well known for its role in metabolism. Lys20 was initially described as homocitrate synthase (HCS), the first enzyme in the lysine biosynthetic pathway in yeast. Its nuclear localization led to the discovery of a key role for Lys20 in DNA damage repair through its interaction with the MYST family histone acetyltransferase Esa1. Overexpression of Lys20 promotes suppression of DNA damage sensitivity of esa1 mutants. In this work, by taking advantage of LYS20 mutants that are active in repair but not in lysine biosynthesis, the mechanism of suppression of esa1 was characterized. First we analyzed the chromatin landscape of esa1 cells, finding impaired histone acetylation and eviction. Lys20 was recruited to sites of DNA damage, and its overexpression promoted enhanced recruitment of the INO80 remodeling complex to restore normal histone eviction at the damage sites. This study improves understanding of the evolutionary, structural and biological relevance of independent activities in a moonlighting protein and links metabolism to DNA damage repair

Reproducibility in forecasting research

The importance of replication has been recognised across many scientific disciplines. Reproducibility is a necessary condition for replicability, because an inability to reproduce results implies that the methods have not been specified sufficiently, thus precluding replication. This paper describes how two independent teams of researchers attempted to reproduce the empirical findings of an important paper, ‘‘Shrinkage estimators of time series seasonal factors and their effect on forecasting accuracy’’ (Miller & Williams, 2003). The two teams proceeded systematically, reporting results both before and after receiving clarifications from the authors of the original study. The teams were able to approximately reproduce each other’s results, but not those of Miller and Williams. These discrepancies led to differences in the conclusions as to the conditions under which seasonal damping outperforms classical decomposition. The paper specifies the forecasting methods employed using a flowchart. It is argued that this approach to method documentation is complementary to the provision of computer code, as it is accessible to a broader audience of forecasting practitioners and researchers. The significance of this research lies not only in its lessons for seasonal forecasting but also, more generally, in its approach to the reproduction of forecasting research

Genetic elimination of field-cage populations of Mediterranean fruit flies

The Mediterranean fruit fly (medfly, Ceratitis capitata Wiedemann) is a pest of over 300 fruits, vegetables and nuts. The sterile insect technique (SIT) is a control measure used to reduce the reproductive potential of populations through the mass release of sterilized male insects that mate with wild females. However, SIT flies can display poor field performance, due to the effects of mass-rearing and of the irradiation process used for sterilization. The development of female-lethal RIDL (release of insects carrying a dominant lethal) strains for medfly can overcome many of the problems of SIT associated with irradiation. Here, we present life-history characterizations for two medfly RIDL strains, OX3864A and OX3647Q. Our results show (i) full functionality of RIDL, (ii) equivalency of RIDL and wild-type strains for life-history characteristics, and (iii) a high level of sexual competitiveness against both wild-type and wild-derived males. We also present the first proof-of-principle experiment on the use of RIDL to eliminate medfly populations. Weekly releases of OX3864A males into stable populations of wild-type medfly caused a successive decline in numbers, leading to eradication. The results show that genetic control can provide an effective alternative to SIT for the control of pest insects

Future land-use change in the Netherlands: an analysis based on a chain of models

Analyses of the impact of European policies on agricultural change are most often based on agricultural sector models. Such models have their limitations: they cannot specify the interaction between agriculture and the rest of the economy, and their spatial dimension is usually limited. Land use simulation models, on the other hand, usually depend on other models for assessing the demand for land. The consistency of those models with the assumptions and databases of the land use model is often not examined. This article reports on a research project where the links between a macroeconomic model, an agricultural sector model and a land use model were explicitly explored in order to arrive at a consistent model chain. This integrated framework was put to the test by applying it to two contrasting scenarios, which compare impact on agricultural incomes, land use and land management.land use, CAP, agricultural policy analyses, Netherlands, Agricultural and Food Policy, Land Economics/Use,

HIV-infected sex workers with beneficial HLA-variants are potential hubs for selection of HIV-1 recombinants that may affect disease progression

Cytotoxic T lymphocyte (CTL) responses against the HIV Gag protein are associated with lowering viremia; however, immune control is undermined by viral escape mutations. The rapid viral mutation rate is a key factor, but recombination may also contribute. We hypothesized that CTL responses drive the outgrowth of unique intra-patient HIV-recombinants (URFs) and examined gag sequences from a Kenyan sex worker cohort. We determined whether patients with HLA variants associated with effective CTL responses (beneficial HLA variants) were more likely to carry URFs and, if so, examined whether they progressed more rapidly than patients with beneficial HLA-variants who did not carry URFs. Women with beneficial HLA-variants (12/52) were more likely to carry URFs than those without beneficial HLA variants (3/61) (p < 0.0055; odds ratio = 5.7). Beneficial HLA variants were primarily found in slow/standard progressors in the URF group, whereas they predominated in long-term non-progressors/survivors in the remaining cohort (p = 0.0377). The URFs may sometimes spread and become circulating recombinant forms (CRFs) of HIV and local CRF fragments were over-represented in the URF sequences (p < 0.0001). Collectively, our results suggest that CTL-responses associated with beneficial HLA variants likely drive the outgrowth of URFs that might reduce the positive effect of these CTL responses on disease progression

Enhanced protein-energy provision via the enteral route in critically ill patients: a single center feasibility trial of the PEP uP protocol

INTRODUCTION: The purpose of this pilot study is to assess the feasibility, acceptability, and safety of a new feeding protocol designed to enhance the delivery of enteral nutrition (EN). METHODS: In a prospective before and after study, we evaluated a new protocol compared to our standard feeding protocol. Innovative elements of the new protocol included setting daily volume based goals instead of hourly rate targets, initiating motility agents and protein supplements on Day 1, liberalizing the gastric residual volume threshold, and the option to use trophic feeds. Bedside nurses filled out questionnaires to assess the acceptability of the new approach and we assessed patients' nutritional and clinical outcomes. RESULTS: We enrolled 20 mechanically ventilated patients who stayed in the Intensive Care Unit for more than three days in the before group and 30 such patients in the after group. On a scale where 1 = totally unacceptable and 10 = totally acceptable, 30 nurses rated the new protocol as 7.1 (range 1 to 10) and no incidents compromising patient safety were observed. In the before group, on average, patients received 58.8% of their energy and 61.2% of their protein requirements by EN compared to 67.9% and 73.6% in the after group (P = 0.33 and 0.13). When the subgroup of patients prescribed to receive full volume feeds in the after group were evaluated (n = 18), they received 83.2% and 89.4% of their energy and protein requirements by EN respectively (P = 0.02 for energy and 0.002 for protein compared to the before group). The rates of vomiting, regurgitation, aspiration, and pneumonia were similar between the two groups. CONCLUSIONS: This new feeding protocol seems to be safe and acceptable to critical care nurses. The adoption of this protocol may be associated with enhanced delivery of EN but further trials are warranted to evaluate its effect on nutritional and clinical endpoints. TRIAL REGISTRATION: ClinicalTrials.gov NCT0110234