A comparison of the results from intra-pleural and intra-peritoneal studies with those from inhalation and intratracheal tests for the assessment of pulmonary responses to inhalable dusts and fibres.

The aim of this paper is to compare results from inhalation studies with those from intraperitoneal and intrapleural tests, where available, for a number of fibrous and particulate test materials. The objective is to determine how well intraperitoneal/intrapleural studies predict the pathological responses observed in more standard in vivo studies of pulmonary toxicity, with a particular focus on carcinogenicity. Published toxicity data was obtained for a number of materials including asbestos, wollastonite, MMVFs (including glass fibres, stone wools and RCF), silicon carbide whiskers, potassium octatitanate, quartz, kevlar, polypropylene and titanium dioxide. For some of the fibrous material reviewed, there is conformity between the results of intraperitoneal and inhalation tests such that they are either consistently positive or consistently negative. For the remaining fibrous materials reviewed, intraperitoneal and inhalation tests give different results, with positive results in the intraperitoneal test not being reflected by positive inhalation results. It is suggested that the intraperitoneal test can be used to exonerate a dust or fibre (because if negative in the intraperitoneal test it is extremely unlikely to be positive in either inhalation or intratracheal tests) but should not be used to positively determine that a dust or fibre is carcinogenic by inhalation. We would argue against the use of intraperitoneal tests for human health risk assessment except perhaps for the purpose of exoneration of a material from classification as a carcinogen.Peer reviewedFinal Accepted Versio

An automatic adaptive method to combine summary statistics in approximate Bayesian computation

To infer the parameters of mechanistic models with intractable likelihoods, techniques such as approximate Bayesian computation (ABC) are increasingly being adopted. One of the main disadvantages of ABC in practical situations, however, is that parameter inference must generally rely on summary statistics of the data. This is particularly the case for problems involving high-dimensional data, such as biological imaging experiments. However, some summary statistics contain more information about parameters of interest than others, and it is not always clear how to weight their contributions within the ABC framework. We address this problem by developing an automatic, adaptive algorithm that chooses weights for each summary statistic. Our algorithm aims to maximize the distance between the prior and the approximate posterior by automatically adapting the weights within the ABC distance function. Computationally, we use a nearest neighbour estimator of the distance between distributions. We justify the algorithm theoretically based on properties of the nearest neighbour distance estimator. To demonstrate the effectiveness of our algorithm, we apply it to a variety of test problems, including several stochastic models of biochemical reaction networks, and a spatial model of diffusion, and compare our results with existing algorithms

Evaluation of outreach interventions for under 16 year olds. Tools and guidance for higher education providers

During 2017-18, OFFA commissioned research that aimed to understand the nature of outreach activities for under 16 year olds (which were funded through access and participation investment) and how these were evaluated. This document, developed from the research, is intended to act as a resource for pre-16 outreach practitioners and evaluators, drawing both on the data collected by this project and the wider literature around evaluation and outreach. It seeks to recognise the complexity of pre-16 outreach work and eschews a prescriptive approach in favour of establishing important principles and actions that are likely to underpin good practice. Our discussion is broadly positioned within a ‘social realist’ worldview (Archer, 2008; Pawson, 2013) that seeks to understand the fuzzy nature of the cause-and-effect relationships that exist within complex social fields, where individuals construct their own realities in reference to those around them. There is a particular focus on epistemology – the pathways to creating dependable, if contingent, knowledge – as a vehicle for making meaning from data that is usually incomplete, compromised or mediated through young people’s emergent constructions of their worlds. Fundamentally, outreach is predicated on the ability of practitioners to influence young people in a planned way, albeit that the plan will not always work for every young person in every cohort. An important element in this epistemology is that it is not concerned with finding single ‘solutions’ that exist outside time and context. Rather, it is concerned with understanding how young people are influenced by their life experiences – not ‘what works’, but what works in a given context and, importantly, why. It is only through understanding the latter element that practices can become robustly effective in the long-term and potentially transferable to other contexts. This is particularly appropriate to pre-16 outreach work due to the lengthy time lag between activity and application to higher education (HE).Office for Students (OfS

Understanding the evaluation of access and participation outreach interventions for under 16 year olds

The project team was asked to address the following six research questions and these were used to guide the project: 1. What are the intended outcomes for current outreach interventions directed at under 16 year olds from disadvantaged backgrounds where the long-term aim is to widen access to higher education (HE)? 2. What types of outreach intervention activity or activities are institutions using in relation to intended outcomes? 3. What evaluation tools, methods and metrics are being used to measure the intended outcomes? 4. What are the perceived and actual challenges and barriers for different stakeholders to effective evaluation of long-term outreach? 5. What do different stakeholders consider most effective evaluation practice and why? 6. How valid and suitable are the evaluation tools, methods and metrics (identified through the research) that are commonly used? The project was constructed around six interlinked work packages: 1. A quantitative analysis of what higher education providers (HEPs) say about their pre-16 outreach activities (and their evaluation) in their 2017-18 access agreements (as the most recent available). 2. An online survey of HEPs to gather information about the pre-16 outreach activities delivered during the 2016-17 academic year and their evaluation, as well as the structure of their evaluation resources and challenges faced. 3. Case studies of four HEPs identified as demonstrating elements of good practice through their access agreements and the online survey, derived from telephone interviews with key staff and documentary analysis. 4. Telephone interviews with 11 third sector organisations (TSOs) to explore their practices and the evaluation of their activities, providing a counterpoint to the data collected from higher education institutions (HEIs). 5. A synthesis of the four preceding work packages to explore elements of good practice, determine a basis for assessing the quality of evaluations and highlight challenges for the sector and OFFA. 6. An invited participatory workshop for evaluators from HEPs and TSOs identified as demonstrating elements of good practice through the online survey and telephone interviews, to act as a sounding board for the emerging conclusions and recommendations.Office for Students (OfS

Characterising the tumour morphological response to therapeutic intervention:an ex vivo model

In cancer, morphological assessment of histological tissue samples is a fundamental part of both diagnosis and prognosis. Image analysis offers opportunities to support that assessment through quantitative metrics of morphology. Generally, morphometric analysis is carried out on two dimensional tissue section data and so only represents a small fraction of any tumour. We present a novel application of three-dimensional (3D) morphometrics for 3D imaging data obtained from tumours grown in a culture model. Minkowski functionals, a set of measures that characterise geometry and topology in n-dimensional space, are used to quantify tumour topology in the absence of and in response to therapeutic intervention. These measures are used to stratify the morphological response of tumours to therapeutic intervention. Breast tumours are characterised by estrogen receptor (ER) status, human epidermal growth factor receptor (HER)2 status and tumour grade. Previously, we have shown that ER status is associated with tumour volume in response to tamoxifen treatment ex vivo. Here, HER2 status is found to predict the changes in morphology other than volume as a result of tamoxifen treatment ex vivo. Finally, we show the extent to which Minkowski functionals might be used to predict tumour grade.Minkowski functionals are generalisable to any 3D data set, including in vivo and cellular systems. This quantitative topological analysis can provide a valuable link among biomarkers, drug intervention and tumour morphology that is complementary to existing, non-morphological measures of tumour response to intervention and could ultimately inform patient treatment

How reliable and robust are current biomarkers for copper status?

Cu is an essential nutrient for man, but can be toxic if intakes are too high. In sensitive populations, marginal over- or under-exposure can have detrimental effects. Malnourished children, the elderly, and pregnant or lactating females may be susceptible for Cu deficiency. Cu status and exposure in the population can currently not be easily measured, as neither plasma Cu nor plasma cuproenzymes reflect Cu status precisely. Some blood markers (such as ceruloplasmin) indicate severe Cu depletion, but do not inversely respond to Cu excess, and are not suitable to indicate marginal states. A biomarker of Cu is needed that is sensitive to small changes in Cu status, and that responds to Cu excess as well as deficiency. Such a marker will aid in monitoring Cu status in large populations, and will help to avoid chronic health effects (for example, liver damage in chronic toxicity, osteoporosis, loss of collagen stability, or increased susceptibility to infections in deficiency). The advent of high-throughput technologies has enabled us to screen for potential biomarkers in the whole proteome of a cell, not excluding markers that have no direct link to Cu. Further, this screening allows us to search for a whole group of proteins that, in combination, reflect Cu status. The present review emphasises the need to find sensitive biomarkers for Cu, examines potential markers of Cu status already available, and discusses methods to identify a novel suite of biomarker

Returning home: heritage work among the Stl'atl'imx of the Lower Lillooet River Valley

This article focusses on heritage practices in the tensioned landscape of the Stl’atl’imx (pronounced Stat-lee-um) people of the Lower Lillooet River Valley, British Columbia, Canada. Displaced from their traditional territories and cultural traditions through the colonial encounter, they are enacting, challenging and remaking their heritage as part of their long term goal to reclaim their land and return ‘home’. I draw on three examples of their heritage work: graveyard cleaning, the shifting ‘official’/‘unofficial’ heritage of a wagon road, and marshalling of the mountain named Nsvq’ts (pronounced In-SHUCK-ch) in order to illustrate how the past is strategically mobilised in order to substantiate positions in the present. While this paper focusses on heritage in an Indigenous and postcolonial context, I contend that the dynamics of heritage practices outlined here are applicable to all heritage practices

Diphthamide modification of eEF2 requires a J-domain protein and is essential for normal development

The intracellular target of diphtheria toxin is a modified histidine residue, diphthamide, in the translation elongation factor, eEF2. This enigmatic modification occurs in all eukaryotes, and is produced in yeast by the action of five gene products, DPH1 to DPH5. Sequence homologues of these genes are present in all sequenced eukaryotic genomes and in higher eukaryotes there is functional evidence for DPH1, 2, 3, and 5 acting in diphthamide biosynthesis. We have identified a mouse mutant in the remaining gene, Dph4. Cells derived from homozygous mutant embryos lack the diphthamide modification of EF2 and are resistant to killing by diphtheria toxin. Reporter-tagged DPH4 protein localizes to the cytoskeleton, in contrast to the localization of DPH1, and consistent with evidence that DPH4 is not part of a proposed complex containing DPH1, 2 and 3. Mice homozygous for the mutation are retarded in growth and development and almost always die before birth. Those that survive long enough have preaxial polydactyly, a duplication of digit 1 of the hind foot. This same defect is seen in embryos homozygous for mutation of DPH1, suggesting that lack of diphthamide on eEF2 could result in translational failure of specific proteins, rather than a generalized translation downregulation