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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.

Summary Transmissible cancers are malignant cells that can spread between individuals of a population, akin to both a parasite and a mobile graft. The survival of the Tasmanian devil, the largest remaining marsupial carnivore, is threatened by the remarkable emergence of two independent lineages of transmissible cancer, devil facial tumour (DFT) 1 and devil facial tumour 2 (DFT2). To aid the development of a vaccine and to interrogate how histocompatibility barriers can be overcome, we analysed the peptides bound to major histocompatibility complex class I (MHC‐I) molecules from Tasmanian devil cells and representative cell lines of each transmissible cancer. Here, we show that DFT1 + IFN‐γ and DFT2 cell lines express a restricted repertoire of MHC‐I allotypes compared with fibroblast cells, potentially reducing the breadth of peptide presentation. Comparison of the peptidomes from DFT1 + IFNγ, DFT2 and host fibroblast cells demonstrates a dominant motif, despite differences in MHC‐I allotypes between the cell lines, with preference for a hydrophobic leucine residue at position 3 and position Ω of peptides. DFT1 and DFT2 both present peptides derived from neural proteins, which reflects a shared cellular origin that could be exploited for vaccine design. These results suggest that polymorphisms in MHC‐I molecules between tumours and host can be ‘hidden’ by a common peptide motif, providing the potential for permissive passage of infectious cells and demonstrating complexity in mammalian histocompatibility barriers., The Tasmanian devil has two independent transmissible cancers that circulate in the population. We have characterized the immunopeptidomes of both cancers and host cell line. We find that the cancers and host cell lines have a common peptide motif.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) is believed to be associated with childhood obesity, although the strength of the association is unknown. METHODS: We performed a cohort study using routine data from health screening examinations at primary school entry (5–6 years old) in Scotland, linked to a nationwide hospital admissions database. A subgroup had a further screening examination at primary school exit (11–12 years old). RESULTS: BMI was available for 597 017 children at 5 to 6 years old in school and 39 468 at 11 to 12 years old. There were 4.26 million child-years at risk for SCFE. Among children with obesity at 5 to 6 years old, 75% remained obese at 11 to 12 years old. There was a strong biological gradient between childhood BMI at 5 to 6 years old and SCFE, with the risk of disease increasing by a factor of 1.7 (95% confidence interval [CI] 1.5–1.9) for each integer increase in BMI z score. The risk of SCFE was almost negligible among children with the lowest BMI. Those with severe obesity at 5 to 6 years old had 5.9 times greater risk of SCFE (95% CI 3.9–9.0) compared with those with a normal BMI; those with severe obesity at 11 to 12 years had 17.0 times the risk of SCFE (95% CI 5.9–49.0). CONCLUSIONS: High childhood BMI is strongly associated with SCFE. The magnitude of the association, temporal relationship, and dose response added to the plausible mechanism offer the strongest evidence available to support a causal association.

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 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.

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.

By the mid-1980s nucleic-acid based methods were penetrating the farthest reaches of biological science, triggering rivalries among practitioners, altering relationships among subfields, and transforming the research front. This article delivers a "bottom up" analysis of that transformation at work in one important area of biological science, plant pathology, by tracing the "molecularization" of efforts to understand and control one notorious plant disease—the late blight of potatoes. It mobilizes the research literature of late blight science as a tool through which to trace the changing typography of the research front from 1983 to 2003. During these years molecularization intensified the traditional fragmentation of the late blight research community, even as it dramatically integrated study of the causal organism into broader areas of biology. In these decades the pathogen responsible for late blight, the oomycete Phytophthora infestans, was discovered to be undergoing massive, frightening, and still largely unexplained genetic diversification—a circumstance that lends the episode examined here an urgency that reinforces its historiographical significance as a casestudy in the molecularization of the biological sciences.

Background Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer. Results We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2–3 μM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 μM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor α, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR α phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-α expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-α. Conclusion These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

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.

Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer. We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2–3 μM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 μM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor α, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR α phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-α expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-α. These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer.

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

THE SOCIOLOGIST AVRAHAM ZLOCZOWER produced his remarkable master's thesis, "Career Opportunities and the Growth of Scientific Discovery in Nineteenth-Century Germany, with Special Reference to Physiology," in 1960. His basic argument became widely known during the next few years through journal articles written by Zloczower himself and by his thesis director, Joseph Ben-David, and in 1973 the thesis was published in German translation.' The Zloczower thesis represents the most ambitious and persuasive attempt yet made to demonstrate quantitatively that scientific creativity is governed by institutional factors and career motivations external to the cognitive features of the science. In this essay we point out that the original Zloczower argument implicitly contains a "weak" and a "strong" version of his central thesis, each appealing to somewhat different evidence, and we advance a tentative criticism of the strong version. Since most readers are unfamiliar with the detailed evidence on which Zloczower's thesis rests, we begin with a summary that stresses more clearly than did the original the quantitative relationships central to the argument. We acknowledge, however, that our summary hardly does justice to the richness of Zloczower's original, which draws on comparisons between German physiology and that of other nations, and which appeals extensively to historical testimony of the physiologists of the day. Zloczower begins his analysis by assembling a numerical index of scientific creativity or research achievement, specifically the number of "discoveries" or

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.

The term ‘Ohm's law’ traditionally denotes the formula of Georg Simon Ohm relating voltage, current, and resistance in metallic conductors. But to students of sensory physiology and its history, ‘Ohm's law’ also denotes another relationship: the fundamental principle of auditory perception that Ohm announced in 1843. This aspect of Ohm's science has attracted very little attention, partly because his galvanic researches so thoroughly eclipsed it in success and importance, and partly because Ohm's work in physiological acoustics had so little immediate impact on the science of his time. On announcing his hypothesis in 1843, Ohm found himself drawn into a bitter dispute with the physicist August Seebeck, who successfully discredited the hypothesis and forced Ohm to withdraw from the field.