Influence of dna repair on nonlinear dose-responses for mutation

Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075μg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O6-methylguanine (O6MeG) by the suicide enzyme O6MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis. © The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved

Food supply depends on seagrass meadows in the coral triangle

The tropical seascape provides food and livelihoods to hundreds of millions of people, but the support of key habitats to this supply remains ill appreciated. For fisheries and conservation management actions to help promote resilient ecosystems, sustainable livelihoods, and food supply, knowledge is required about the habitats that help support fisheries productivity and the consequences of this for food security. This paper provides an interdisciplinary case study from the coral triangle of how seagrass meadows provide support for fisheries and local food security. We apply a triangulated approach that utilizes ecological, fisheries and market data combined with over 250 household interviews. Our research demonstrates that seagrass associated fauna in a coral triangle marine protected area support local food supply contributing at least 50% of the fish based food. This formed between 54% and 99% of daily protein intake in the area. Fishery catch was found to significantly vary with respect to village (p < 0.01) with habitat configuration a probable driver. Juvenile fish comprised 26% of the fishery catch and gear type significantly influenced this proportion (<0.05). Limited sustainability of fishery practices (high juvenile catch and a 51% decline in CPUE for the biggest fishery) and poor habitat management mean the security of this food supply has the potential to be undermined in the long-term. Findings of this study have implications for the management and assessment of fisheries throughout the tropical seascape. Our study provides an exemplar for why natural resource management should move beyond biodiversity and consider how conservation and local food security are interlinked processes that are not mutually exclusive. Seagrass meadows are under sustained threat worldwide, this study provides evidence of the need to conserve these not just to protect biodiversity but to protect food security

Symbiont-mediated RNA interference in insects

RNA interference (RNAi) methods for insects are often limited by problems with double-stranded (ds) RNA delivery, which restricts reverse genetics studies and the development of RNAi-based biocides. We therefore delegated to insect symbiotic bacteria the task of: (i) constitutive dsRNA synthesis and (ii) trauma-free delivery. RNaseIII-deficient, dsRNA-expressing bacterial strains were created from the symbionts of two very diverse pest species: a long-lived blood-sucking bug, Rhodnius prolixus, and a short-lived globally invasive polyphagous agricultural pest, western flower thrips (Frankliniella occidentalis). When ingested, the manipulated bacteria colonized the insects, successfully competed with the wild-type microflora, and sustainably mediated systemic knockdown phenotypes that were horizontally transmissible. This represents a significant advance in the ability to deliver RNAi, potentially to a large range of non-model insects

Negatively-Marked MCQ Assessments That Reward Partial Knowledge Do Not Introduce Gender Bias Yet Increase Student Performance and Satisfaction and Reduce Anxiety

Multiple-choice question (MCQ) examinations are increasingly used as the assessment method of theoretical knowledge in large class-size modules in many life science degrees. MCQ-tests can be used to objectively measure factual knowledge, ability and high-level learning outcomes, but may also introduce gender bias in performance dependent on topic, instruction, scoring and difficulty. The ‘Single Answer’ (SA) test is often used in which students choose one correct answer, in which they are unable to demonstrate partial knowledge. Negatively marking eliminates the chance element of guessing but may be considered unfair. Elimination testing (ET) is an alternative form of MCQ, which discriminates between all levels of knowledge, while rewarding demonstration of partial knowledge. Comparisons of performance and gender bias in negatively marked SA and ET tests have not yet been performed in the life sciences. Our results show that life science students were significantly advantaged by answering the MCQ test in elimination format compared to single answer format under negative marking conditions by rewarding partial knowledge of topics. Importantly, we found no significant difference in performance between genders in either cohort for either MCQ test under negative marking conditions. Surveys showed that students generally preferred ET-style MCQ testing over SA-style testing. Students reported feeling more relaxed taking ET MCQ and more stressed when sitting SA tests, while disagreeing with being distracted by thinking about best tactics for scoring high. Students agreed ET testing improved their critical thinking skills. We conclude that appropriately-designed MCQ tests do not systematically discriminate between genders. We recommend careful consideration in choosing the type of MCQ test, and propose to apply negative scoring conditions to each test type to avoid the introduction of gender bias. The student experience could be improved through the incorporation of the elimination answering methods in MCQ tests via rewarding partial and full knowledge

Local Modelling Techniques for Assessing Micro-Level Impacts of Risk Factors in Complex Data: Understanding Health and Socioeconomic Inequalities in Childhood Educational Attainments

Although inequalities in health and socioeconomic status have an important influence on childhood educational performance, the interactions between these multiple factors relating to variation in educational outcomes at micro-level is unknown, and how to evaluate the many possible interactions of these factors is not well established. This paper aims to examine multi-dimensional deprivation factors and their impact on childhood educational outcomes at micro-level, focusing on geographic areas having widely different disparity patterns, in which each area is characterised by six deprivation domains (Income, Health, Geographical Access to Services, Housing, Physical Environment, and Community Safety). Traditional health statistical studies tend to use one global model to describe the whole population for macro-analysis. In this paper, we combine linked educational and deprivation data across small areas (median population of 1500), then use a local modelling technique, the Takagi-Sugeno fuzzy system, to predict area educational outcomes at ages 7 and 11. We define two new metrics, “Micro-impact of Domain” and “Contribution of Domain”, to quantify the variations of local impacts of multidimensional factors on educational outcomes across small areas. The two metrics highlight differing priorities. Our study reveals complex multi-way interactions between the deprivation domains, which could not be provided by traditional health statistical methods based on single global model. We demonstrate that although Income has an expected central role, all domains contribute, and in some areas Health, Environment, Access to Services, Housing and Community Safety each could be the dominant factor. Thus the relative importance of health and socioeconomic factors varies considerably for different areas, depending on the levels of each of the other factors, and therefore each component of deprivation must be considered as part of a wider system. Childhood educational achievement could benefit from policies and intervention strategies that are tailored to the local geographic areas' profiles

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Temporal Changes in Patient-Matched Staphylococcus epidermidis Isolates from Infections: towards Defining a ‘True’ Persistent Infection

Staphylococcus epidermidis is found naturally on the skin but is a common cause of persistent orthopaedic device-related infections (ODRIs). This study used a pan-genome and gene-by-gene approach to analyse the clonality of whole genome sequences (WGS) of 115 S. epidermidis isolates from 55 patients with persistent ODRIs. Analysis of the 522 gene core genome revealed that the isolates clustered into three clades, and MLST analysis showed that 83% of the isolates belonged to clonal complex 2 (CC2). Analysis also found 13 isolate pairs had different MLST types and less than 70% similarity within the genes; hence, these were defined as re-infection by a different S. epidermidis strain. Comparison of allelic diversity in the remaining 102 isolates (49 patients) revealed that 6 patients had microevolved infections (&gt;7 allele differences), and only 37 patients (77 isolates) had a &lsquo;true&rsquo; persistent infection. Analysis of the core genomes of isolate pairs from 37 patients found 110/841 genes had variations; mainly in metabolism associated genes. The accessory genome consisted of 2936 genes; with an average size of 1515 genes. To conclude, this study demonstrates the advantage of using WGS for identifying the accuracy of a persistent infection diagnosis. Hence, persistent infections can be defined as &lsquo;true&rsquo; persistent infections if the core genome of paired isolates has &le;7 allele differences; microevolved persistent infection if the paired isolates have &gt;7 allele differences but same MLST type; and polyclonal if they are the same species but a different MLST type

Data from: Symbiont-mediated RNA interference in insects

RNA interference (RNAi) methods for insects are often limited by problems with double-stranded (ds) RNA delivery, which restricts reverse genetics studies and the development of RNAi-based biocides. We therefore delegated to insect symbiotic bacteria the task of: (i) constitutive dsRNA synthesis and (ii) trauma-free delivery. RNaseIII-deficient, dsRNA-expressing bacterial strains were created from the symbionts of two very diverse pest species: a long-lived blood-sucking bug, Rhodnius prolixus, and a short-lived globally invasive polyphagous agricultural pest, Western Flower Thrips (Frankliniella occidentalis). When ingested, the manipulated bacteria colonized the insects, successfully competed with the wildtype microflora, and sustainably mediated systemic knockdown phenotypes that were horizontally transmissible. This represents a significant advance in the ability to deliver RNAi, potentially to a large range of non-model insects

Data from: Symbiont-mediated RNA interference in insects

RNA interference (RNAi) methods for insects are often limited by problems with double-stranded (ds) RNA delivery, which restricts reverse genetics studies and the development of RNAi-based biocides. We therefore delegated to insect symbiotic bacteria the task of: (i) constitutive dsRNA synthesis and (ii) trauma-free delivery. RNaseIII-deficient, dsRNA-expressing bacterial strains were created from the symbionts of two very diverse pest species: a long-lived blood-sucking bug, Rhodnius prolixus, and a short-lived globally invasive polyphagous agricultural pest, Western Flower Thrips (Frankliniella occidentalis). When ingested, the manipulated bacteria colonized the insects, successfully competed with the wildtype microflora, and sustainably mediated systemic knockdown phenotypes that were horizontally transmissible. This represents a significant advance in the ability to deliver RNAi, potentially to a large range of non-model insects