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Antigen processing is an immunological mechanism by which intracellular peptides are transported to the cell surface while bound to Major Histocompatibility Complex molecules, where they can be surveyed by circulating CD8+ or CD4+ T-cells, potentially triggering an immunological response. The antigen processing pathway is a complex multistage filter that refines a huge pool of potential peptide ligands derived from protein degradation into a smaller ensemble for surface presentation. Each stage presents unique challenges due to the number of ligands, the polymorphic nature of MHC and other protein constituents of the pathway and the nature of the interactions between them. Predicting the ensemble of displayed peptide antigens, as well as their immunogenicity, is critical for improving T cell vaccines against pathogens and cancer. Our predictive abilities have always been hindered by an incomplete empirical understanding of the antigen processing pathway. In this review, we highlight the role of computational and structural approaches in improving our understanding of antigen processing, including structural biology, computer simulation, and machine learning techniques, with a particular focus on the MHC-I pathway.

Renal Fanconi syndrome (RFS) is a generalised disorder of the proximal convoluted tubule. Many genes have been associated with RFS including those that cause systemic disorders such as cystinosis, as well as isolated RFS. We discuss the case of a 10-year-old female who presented with leg pain and raised creatinine on a screening blood test. Her mother has RFS and required a kidney transplant in her thirties. Further investigations confirmed RFS in the daughter. Exome sequencing was performed on the affected mother, child, and unaffected father. We identified a novel variant in GATM; c.965GC p.(Arg322Pro) segregating dominantly in the mother and daughter. We validated our finding with molecular dynamics simulations and demonstrated a dynamic signature that differentiates our variant and two previously identified pathogenic variants in GATM from wildtype. Genetic testing has uncovered a novel pathogenic variant that predicts progression to end stage kidney failure and has important implications for family planning and cascade testing. We recommend that GATM is screened for in children presenting with RFS, in addition to adults, particularly with kidney failure, who may have had previous negative gene testing.

Purpose This paper aims to set out to share the reflections of safeguarding adult board managers as they worked through what is likely to be just the first wave of the coronavirus COVID-19 pandemic. Design/methodology/approach The paper draws on the experience of small number of safeguarding adult board managers who have provided reflections from practice. Findings This paper illustrates just some of the responses developed by safeguarding adult board managers and their boards to continue to deliver the work of safeguarding those at risk of abuse and harm in the face of unprecedented impact of the coronavirus COVID-19 pandemic on a key aspect of the safeguarding adult system in England. Originality/value The reflections reported here are not intended to offer a representative commentary on the experiences of those who oversee and manage safeguarding adults’ boards. It is intention to provide a flavour of some of the challenges and dilemmas faced and some of the creative solutions to address them used by one group of adult safeguarding practitioners.

The importance of magnetic cleanliness and inflight compensation to account for fluctuations in magnetic field is a recognized concern within the space industry. Their effects must be considered, minimized, and where necessary compensated throughout the development of any spacecraft, their subsystems, and while in flight. This is just as true within the context of the laser interferometer space antenna pathfinder mission, where sensitive gravitational wave telemetry systems are vulnerable to magnetic disturbances. In collaboration with the Science and Technology Facility Council, Rutherford Appleton Laboratory, Bartington Instruments, and the National Physical Laboratory (NPL), a compact low-noise gradiometer was developed under European Space Agency contract reference AO/1-6085/09/NL/AF. Such a versatile device will be used on the ground to assess the magnetic cleanliness of spacecraft and also inflight, to monitor changes in the local magnetic field. This paper introduces the capabilities developed by NPL, specifically for the calibration of the compact low-noise fluxgate gradiometer. The procedures used to test and calibrate the novel gradiometer will be discussed in detail, including a range of Helmholtz coils, gradient coils (used to generate known diagonal and off-diagonal gradients), and shielding techniques. These technologies were combined to establish key parameters, such as low frequency noise, offset, gain and gradient sensitivity, with specific attention given to the off-diagonal terms of the gradient tensor matrix.

Existing measurement facilities do not allow the characterization of magnetic sensors at the operational temperatures encountered in a range of industrial applications. Routine calibration of such sensors can be carried out by various facilities, but are limited to ambient laboratory temperatures only. The National Physical Laboratory (NPL) has developed measurement facilities for the characterization of these sensors over a temperature range of −55 °C to +125 °C reflecting the actual temperatures experienced during their operation. This paper will describe the development of the traceable measurement systems at NPL that enables this characterization and will present results for fluxgate and AMR type sensors.

Maternal nutritional status during pregnancy has been reported to be associated with childhood asthma and atopic disease. The Avon Longitudinal Study of Parents and Children has reported associations between reduced umbilical cord Fe status and childhood wheeze and eczema; however, follow-up was short and lung function was not measured. In the present study, the associations between maternal Fe status during pregnancy and childhood outcomes in the first 10 years of life were investigated in a subgroup of 157 mother–child pairs from a birth cohort with complete maternal, fetal ultrasound, blood and child follow-up data. Maternal Fe intake was assessed using FFQ at 32 weeks of gestation and Hb concentrations and serum Fe status (ferritin, soluble transferrin receptor and TfR-F (transferrin receptor:ferritin) index) were measured at 11 weeks of gestation and at delivery. Maternal Fe intake, Hb concentrations and serum Fe status were found to be not associated with fetal or birth measurements. Unit increases in first-trimester maternal serum TfR concentrations (OR 1·44, 95 % CI 1·05, 1·99) and TfR-F index (OR 1·42, 95 % CI 1·10, 1·82) (i.e. decreasing Fe status) were found to be associated with an increased risk of wheeze, while unit increases in serum ferritin concentrations (i.e. increasing Fe status) were found to be associated with increases in standardised mean peak expiratory flow (PEF) (β 0·25, 95 % CI 0·09, 0·42) and forced expiratory volume in the first second (FEV1) (β 0·20, 95 % CI 0·08, 0·32) up to 10 years of age. Increasing maternal serum TfR-F index at delivery was found to be associated with an increased risk of atopic sensitisation (OR 1·35, 95 % CI 1·02, 1·79). The results of the present study suggest that reduced maternal Fe status during pregnancy is adversely associated with childhood wheeze, lung function and atopic sensitisation, justifying further studies on maternal Fe status and childhood asthma and atopic disease.

RATIONALE: Advances in spirometry measurement techniques have made it possible to obtain measurements in children as young as 3 years of age; however, in practice, application remains limited by the lack of appropriate reference data for young children, which are often based on limited population-specific samples. OBJECTIVES: We aimed to build on previous models by collating existing reference data in young children (aged 3-7 years), to produce updated prediction equations that span the preschool years and that are also linked to established reference equations for older children and adults. METHODS: The Asthma UK Collaborative initiative was established to collate lung function data from healthy young children aged 3-7 years. Collaborators included researchers with access to pulmonary function test data in healthy preschool children. Spirometry centiles were created using the LMS (Lambda-Mu-Sigma) method and extend previously published equations down to 3 years of age. MAIN RESULTS: The Asthma UK centiles charts for spirometry are based on the largest sample of healthy young Caucasian children aged 3-7 years (n=3777) from 15 centers across 11 countries and provide a continuous reference with a smooth transition into adolescence and adulthood. These equations improve existing pediatric equations by considering the between-subject variability to define a more appropriate age-dependent lower limit of normal. The collated dataset reflects a variety of equipment, measurement protocols and population characteristics and may be generalizable across different populations. CONCLUSIONS: We present prediction equations for spirometry for preschool children and provide a foundation which will facilitate continued updating.

The 1980s saw the rise of the public understanding of science, as a movement and as a research field. The decade also saw the goal of K-12 science instruction reoriented toward the promotion of scientific literacy for all students. This paper explores the subsequent relationship of these two movements. It examines debates over K-12 science curricular reform, with particular focus on “civic scientific literacy,” the introduction of science, technology, and society (STS) issues into classrooms, and the gradual retreat from STS-oriented reforms. It discusses how those debates may have been influenced by findings from the public understanding of science, and argues that educational debates themselves provide an important resource for probing larger issues of public understanding.

The late blight disease of potatoes, which triggered the great Irish famine of 1845-1849, remains one of the most feared and intractable plant diseases today. Decades of dispute about the cause of the disease followed the outbreak of 1845, and the scientifi c controversy illustrates the uneasy historical relationship among farmers, scientifi c agronomists, and plant pathologists. Consensus fi nally emerged that the fungus Phytophthora infestans was the true cause of the disease, but that organism's full life cycle remained obscure. Its sexual oospores could not be readily obtained by mycologists, despite sporadic reports that had been observed. The 20th century opened with great optimism that resistant varieties could be developed using dominant R-genes obtainable from some wild species, and this optimism led to a proliferation of public breeding programs between 1925 and 1935. But these hopes had foundered by the early 1950s with the inexplicable appearance of new fungal races that could overwhelm the most blight-resistant germplasm. The Rockefeller Foundation's postwar agricultural initiative in Mexico led during the 1950s to dramatic and unexpected solutions to some of the late blight puzzles. But even then the fungus remained obscure, and effective, non-chemical control methods have never been forthcoming. This article examines the historical frustrations of late-blight science and advances that history as a case study illustrating the rise and fall of an “heroic age” of resistance breeding and plant pathology in the first half of the 20th century.

On 14 January 1999, the Health Protection Branch of Health Canada denied regulatory approval to the Monsanto Corporation's recombinant bovine growth hormone, Nutrilac. In doing so it rejected the first major product of genetic engineering proposed for regulatory approval in Canada that had been commercially targeted at the agriculture and food-production system. The decision ended a bitter and sometimes bizarre saga characterized by allegations of corporate bribery, whistle-blowing scientists and hostile parliamentary committee investigations. The rBST story is examined here as an example of contemporary technoscientific controversies, as a case study in the Canadian regulatory style and for its relevance to current debates over the reform of Canadian regulatory procedures. Le 14 janvier 1999, la Direction generale de la protection de la santa de Same Canada refusait d'accorder A la societe Monsanto l'approbation reglementaire concemant Nutrilac, son hormone de croissance bovine recombinee. Ce faisant, elle rejetait le premier produit d'importance issu du genie genetique et propose pour approbation reglementaire au Canada, produit qui ciblait, de facon commerciale, l'agriculture et le systeme de la production alimentaire. La decision mettait fin A une saga amere et parfois etrange, caracterisee par des allegations de corruption relatives aux entreprises, par la denonciation des scientifiques et par des enquetes hostiles de comites parlementaires. On examine ici I'histoire du rBST, un bon exemple de controverse technoscientifique contemporaine, en tant qu'etude de cas du style reglementaire canadien, ainsi que pour sa pertinence quant aux debats actuels sur la reforme du systeme reglementaire canadien. Public issues today focus increasingly upon technological innovations, the controversies to which they give rise and the regulatory decisions they necessitate. These controversies usually involve risk or the perception of risk, and they raise issues of social justice as to how risks and benefits are to be shared. They differ from other kinds of political and social disputes because they purport to turn on highly technical questions that require expert scientific assessment. Theorists like Dorothy Nelkin have noted that such controversies often see a "displacement of issues" from the political, economic and moral questions that motivate the controversy to a focus on narrowly technical or scientific issues that serve as surrogates. The science behind technoscientific controversies is typically disputed, uncertain and usually insufficient to resolve the dispute or to generate expert consensus. Much of it is what Canadian theorist Liora Salter has called "mandated science" - research done specifically to assist a regulatory decision or to satisfy regulatory requirements. If the research is mandated by government but performed by an initiating manufacturer, it is typically treated as proprietary, confidential and hence unavailable to public scrutiny - one of the several ways in which, according to Salter, mandated science differs in character from academic or research science. The uncertainty that besets much mandated science is inherently political. Uncertainty can justify calls for more research, regulatory delay and so defence of the status quo. Technoscientific controversies are typically dealt with in the science-based, regulatory agencies of government. There they disrupt the low-profile routine of these agencies, thrust them into the public and media spotlight and subject their proceedings to unfamiliar and unwelcome political criticism. They challenge the scientistic assumptions that often prevail in these agencies and so threaten their cognitive authority. No wonder, then, that with technoscientific controversies on the rise, the question of how different agencies within the same governmental structure and comparable regulatory agencies in different governments deal with science-based regulatory controversies has become an urgent question. …

The analysis of technoscientific regulatory controversies is now an established genre within science studies, with a small but important methodological and meta-literature. That literature has only rarely noted how published accounts of particular controversies inevitably employ narrational strategies, including decisions about emplotment, time-frames, character-motivation, and the use of tropes, to endow these stories with political and epistemological meaning. In an exercise designed to recover these narrational elements and promote narrative consciousness, this paper presents two separate accounts of a single important controversy: Canada's recent regulatory experience with the Monsanto Corporation's recombinant bovine somatotropin (rBST). The discussion points out the different narrational strategies employed in each account, and analyses how these strategies interact with explicit or theory-based interpretive approaches to determine how the accounts contribute to `public moral argument' about regulatory affairs. It concludes with broader speculations on the advantages that a greater reliance on narrative form has to offer the field of controversy-analysis and science studies in general.

Programs for the reform of K-12 science teaching today usually insist that science teachers must introduce their students to the nature of science, as well as to scientific content. The academic field of science studies, however, evinces no consensus about what the nature of science really is. This article examines how science educators and educational researchers have drawn on the fragmented teachings of science studies about the nature of science, and how they have used those teachings as a resource in their own projects. It identifies three competing movements for the reform of science teaching that owe a particular debt to science studies: history and philosophy of science (HPS), science, technology, and society (STS), and constructivist pedagogy. The article analyzes some of the deep assumptions about the relationships between research science, school science, and children’s learning that pervade the educational literature.

Precipitates in the form of grain growth inhibitors play an essential role in the production of grain-oriented electrical steels, as they promote the development of Goss texture during secondary recrystallization. However, the presence of precipitates in the final material can have a detrimental effect on loss and permeability, as they impede domain wall motion during the magnetization process. In previous work [ K. Jenkins and M. Lindenmo, J. Magn. Magn. Mater. 320, 2423 (2008) ], a conventional grain-oriented electrical steel was presented that contained very fine precipitates, which did not damage the bulk magnetic properties. In this article the influence of precipitate size is investigated by comparing local Barkhausen noise measurements and electron backscatter diffraction analysis for a number of grain-oriented electrical steels, which are metallurgically similar except for the size and abundance of precipitates.

FORMERLY the history of education consisted largely ofthe Ideengeschichte of pedagogical theory and of narrow admini? strative and inst tutional studies of s hool and universities. More recently, what Konrad Jarausch called the "old 'new history of education'" has turned to different concerns.1 These include the quan? titative analysis of social and institutional structures: comparative studies of school types, student recruitment and mobility patterns, and the developing career structure ofthe teaching corps. The new history of education attempts to unravel the bureaucratic and political struc? tures and debates which accompanied educational reform and its im? plementation. Its theoretical discussions have focussed on middlelevel causation, mainly on attempts to correlate particular pedagogical agendas with specific social interests. Despite its very considerable achievements, the new history of edu? cation is open to criticism for its neglect of how educational reform is rooted in larger patterns of historical change. It has also been criticized

A massive bibliography of works on physiological optics allows an approximate reconstruction of literature production in this science between 1840 and 1894. It shows how relative levels of productivity varied in over seventy constituent problem areas and challenges us to explain the shifting foci of research activity in terms of what is known about the institutional and theoretical development of the field. This paper describes the growth of the science and offers such an interpretation, arguing that physiological optics passed from a `pre-paradigm' to a `paradigm' stage between 1850 and 1870. The elements of the paradigmatic formulation affected literature production in various problem areas differently, depending on the nature of the consensus they imposed, and the formulation did not prevent chronic disagreements on important theoretical questions from re-emerging.