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In this special issue on communication, language and literacy, Helen Freeman talks about the 2021 Oxford Children's Word of the Year and shares some insight on Oxford's latest Children's Language Report, highlighting the role that early years practitioners can play to help children develop the vocabulary they need to thrive.

AIMS/HYPOTHESIS: C57BL/6J mice exhibit impaired glucose tolerance. The aims of this study were to map the genetic loci underlying this phenotype, to further characterise the physiological defects and to identify candidate genes. METHODS: Glucose tolerance was measured in an intraperitoneal glucose tolerance test and genetic determinants mapped in an F2 intercross. Insulin sensitivity was measured by injecting insulin and following glucose disposal from the plasma. To measure beta cell function, insulin secretion and electrophysiological studies were carried out on isolated islets. Candidate genes were investigated by sequencing and quantitative RNA analysis. RESULTS: C57BL/6J mice showed normal insulin sensitivity and impaired insulin secretion. In beta cells, glucose did not stimulate a rise in intracellular calcium and its ability to close KATP channels was impaired. We identified three genetic loci responsible for the impaired glucose tolerance. Nicotinamide nucleotide transhydrogenase (Nnt) lies within one locus and is a nuclear-encoded mitochondrial proton pump. Expression of Nnt is more than sevenfold and fivefold lower respectively in C57BL/6J liver and islets. There is a missense mutation in exon 1 and a multi-exon deletion in the C57BL/6J gene. Glucokinase lies within the Gluchos2 locus and shows reduced enzyme activity in liver. CONCLUSIONS/INTERPRETATION: The C57BL/6J mouse strain exhibits plasma glucose intolerance reminiscent of human type 2 diabetes. Our data suggest a defect in beta cell glucose metabolism that results in reduced electrical activity and insulin secretion. We have identified three loci that are responsible for the inherited impaired plasma glucose tolerance and identified a novel candidate gene for contribution to glucose intolerance through reduced beta cell activity.

This paper reviews recent studies on the role of Nnt (nicotinamide nucleotide transhydrogenase) in insulin secretion and detoxification of ROS (reactive oxygen species). Glucose-stimulated insulin release from pancreatic β-cells is mediated by increased metabolism. This elevates intracellular [ATP], thereby closing K ATP channels (ATP-sensitive potassium channels) and producing membrane depolarization, activation of voltage-gated Ca 2+ channels, Ca 2+ influx and, consequently, insulin secretion. The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion, which results from a naturally occurring deletion in the Nnt gene. Transgenic expression of the wild-type Nnt gene in C57BL/6J mice rescues the phenotype. Knockdown of Nnt in the insulin-secreting cell line MIN6 with small interfering RNA dramatically reduced Ca 2+ influx and insulin secretion. Similarly, mice carrying ENU ( N -ethyl- N -nitrosourea)-induced loss-of-function mutations in Nnt were glucose intolerant and secreted less insulin during a glucose tolerance test. Islets isolated from these mice showed impaired insulin secretion in response to glucose, but not to the K ATP channel blocker tolbutamide. This is explained by the fact that glucose failed to elevate ATP in Nnt mutant islets. Nnt is a nuclear-encoded mitochondrial protein involved in detoxification of ROS. β-Cells isolated from Nnt mutant mice showed increased ROS production on glucose stimulation. We hypothesize that Nnt mutations enhance glucose-dependent ROS production and thereby impair β-cell mitochondrial metabolism, possibly via activation of uncoupling proteins. This reduces ATP production and lowers K ATP channel activity. Consequently, glucose-dependent electrical activity and insulin secretion are impaired.

Critical care pharmacology education is crucial to safe patient care for nurses orienting to specialized areas. Although traditionally taught as a classroom lecture, it is important to consider effectiveness of alternative methods for education. This study provided experimentally derived evidence regarding effectiveness of blended versus traditional lecture for critical care pharmacology education. Regardless of learner demographics, the findings determined no significant differences in cognitive learning outcomes or learner satisfaction between blended versus lecture formats.

The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. The genetic locus underlying this phenotype was mapped to nicotinamide nucleotide transhydrogenase (Nnt) on mouse chromosome 13, a nuclear-encoded mitochondrial protein involved in β-cell mitochondrial metabolism. C57BL/6J mice have a naturally occurring in-frame five-exon deletion in Nnt that removes exons 7–11. This results in a complete absence of Nnt protein in these mice. We show that transgenic expression of the entire Nnt gene in C57BL/6J mice rescues their impaired insulin secretion and glucose-intolerant phenotype. This study provides direct evidence that Nnt deficiency results in defective insulin secretion and inappropriate glucose homeostasis in male C57BL/6J mice.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This paper is being retracted because of concerns with Figures 2B and S3. In Figure S3, the SDS-PAGE gel image had molecular weight markers added from another autoradiograph and additional nonspecific bands obscured or removed. In the top panel of Figure 2, an actin Western blot was used instead of a GCK Western blot. This matter was investigated by the Medical Research Council (UK) under their Scientific Misconduct Policy and Procedures, and scientific misconduct pertaining to the issues described here against the first author Helen Freeman was found. Repetition of these experiments by other group members gave identical results to those shown in the paper. Nevertheless, although we feel that the scientific conclusions of the paper (that loss of NNT impairs insulin secretion and impairs glucose tolerance in C57BL/6J mice) still stand, given the conclusion of scientific misconduct against the first author, the authors think the most responsible course is to retract the paper. The authors sincerely apologize for the inconvenience caused by this retraction.

This article tested the hypothesis that role expectations may constrain or facilitate innovation. The case of female managers provided the context for this. Study 1 examined differential role expectations (for the roles of male and female managers) (N = 55), and Study 2 investigated the constraints of male and female manager roles on solution type and character. Using a focused interview format (N = 20), potential barriers to innovation were also examined. The results suggest that innovative solutions were attributed more often to a male than a female manager, whereas adaptive solutions were attributed more often to a female than a male manager. Risks identified as potential barriers to innovation among female managers included the risk attached to consequences of failure or mistake, the risk of criticism, and the risk of not receiving credit for ideas. However, differential role expectations did not have an impact on the production of actual solutions. The findings are discussed for their potential to co...

Growth hormone (GH) is an anabolic cytokine hormone regulating linear growth in childhood and normal body composition in adults. The current therapeutic regimen for GH replacement requires once-daily subcutaneous injections which is inconvenient and expensive. A number of approaches have been taken to create long-acting preparations, including depot preparations and sustained-release formulations. However, although of proven efficacy, such GH preparations are characterised by a dominant early-release profile, causing supraphysiological GH levels, manufacture is expensive and injections may be painful. There is a need for cytokine formulations that minimise manufacturing costs, have good pharmacokinetic profiles, are easy to administer, and are acceptable to patients. Recent focus has been on the generation of long-acting GH analogues by post-translational modification or protein fusions. In this article, we review the new technologies for generating long-acting GH agonists and GH antagonists including pegylation, albumin fusions and ligand-receptor fusions.

OBJECTIVES— To identify, map, clone, and functionally validate a novel mouse model for impaired glucose tolerance and insulin secretion. RESEARCH DESIGN AND METHODS— Haploinsufficiency of the insulin receptor and associated mild insulin resistance has been used to sensitize an N-ethyl-N-nitrosourea (ENU) screen to identify novel mutations resulting in impaired glucose tolerance and diabetes. The new impaired glucose tolerance 4 (IGT4) model was selected using an intraperitoneal glucose tolerance test and inheritance of the phenotype confirmed by generation of backcross progeny. Segregation of the phenotype was correlated with genotype information to map the location of the gene and candidates sequenced for mutations. The function of the SRY-related high mobility group (HMG)-box 4 (Sox4) gene in insulin secretion was tested using another ENU allele and by small interfering RNA silencing in insulinoma cells. RESULTS— We describe two allelic autosomal dominant mutations in the highly conserved HMG box of the transcription factor Sox4. Previously associated with pancreas development, Sox4 mutations in the adult mouse result in an insulin secretory defect, which exhibits impaired glucose tolerance in association with insulin receptor+/−–induced insulin resistance. Elimination of the Sox4 transcript in INS1 and Min6 cells resulted in the abolition of glucose-stimulated insulin release similar to that observed for silencing of the key metabolic enzyme glucokinase. Intracellular calcium measurements in treated cells indicate that this defect lies downstream of the ATP-sensitive K+ channel (KATP channel) and calcium influx. CONCLUSIONS— IGT4 represents a novel digenic model of insulin resistance coupled with an insulin secretory defect. The Sox4 gene has a role in insulin secretion in the adult β-cell downstream of the KATP channel.

Diabetes is one of the most challenging health problems of the 21st century with an alarming increase in the prevalence of type-2 diabetes mellitus (T2DM) and associated conditions such as hypertension, dyslipidemias and obesity. T2DM is a complex genetic disease comprised of many metabolic disorders with a common phenotype of glucose intolerance. Patients with T2DM would have inherited a variety of different genetic factors that together with environmental factors combine as the primary cause. This complicates the genetic study of the disease and means that different methodological approaches are needed if we hope to identify susceptibility genes and genetic variants. The biochemical and physiological processes that underpin T2DM are still unclear although most certainly involve impairment in insulin secretion and insulin action. In this review, we will discuss the most exciting advances in understanding the genetics of T2DM by looking at recent discoveries employing human association studies and candidate genes arising from animal models.

The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. QTL mapping identified Nicotinamide Nucleotide Transhydrogenase (Nnt), a nuclear-encoded mitochondrial protein thought to be involved in free radical detoxification, as a candidate gene. To investigate its functional role, we used siRNA to knock down Nnt in insulin-secreting MIN6 cells. This produced a dramatic reduction in insulin secretion and the rise in [Ca2+]i evoked by glucose, but not tolbutamide. We identified two ENU-induced point mutations in Nnt (N68K, G745D). Nnt mutant mice were glucose intolerant and secreted less insulin during a glucose tolerance test. Isolated islets showed impaired insulin secretion in response to glucose, but not to tolbutamide, and glucose failed to enhance ATP levels. Glucose utilization and production of reactive oxygen species were increased in Nnt beta cells. We hypothesize that Nnt mutations/deletion uncouple beta cell mitochondrial metabolism leading to less ATP production, enhanced KATP channel activity, and consequently impaired insulin secretion.

This introduction to the New Year service is quoted by a number of rabbis from continental Europe at the start of their sermons on Rosh Hashanah. Some of the 'curses' in question are easy to identify. One is the escalation of violence against Israel in the second Intifada and the accompanying retaliation. But even more dramatic , devastating and chilling was the attack on the World Trade Center in New York and the Pentagon in Washington. The fact that it occurred a few days before the Jewish New Year forced rabbis throughout the world to address this appalling event. Though most were as numbed and shocked as their congregants , theirs was the responsibility to offer what comfort was possible , what understanding could be gleaned and what guidance they could muster at this time when , over and above the normal ' once a year ' community , many others attended services if only to feel the comfort of being together with other Jews at this time of crisis. It occurred to the editors , and subsequently it turned out that the same idea occurred to others , that the sermons delivered at this time would provide an extraordinary ' snapshot ' of how the Jewish world had reacted to this appalling event. We canvassed Liberal, Reform and Conservative colleagues in the UK and continental Europe , most of whom are graduates of the Leo Baeck College. We received some forty responses. A few we publish in this issue as articles (see the Editorial for details). But from the rest we have extracted some of the main themes that were addressed. At the time of editing ( December 2001) we can see that some of the themes showed a degree of prescience about issues that would arise. By the time this appears much else will inevitably have changed. Whether the world has changed forever as the first public reactions suggested , remains to be seen. The scale of the event was new, but , as some writers suggest, it is an all too

In the article listed above, it was discovered that the Western blot in Fig. 1 C was inappropriately manipulated. It appears that a protein band labeled C3H/HeH, which was a control sample, was added to the figure in its preparation. A Medical Research Council investigation found that there had been scientific misconduct by the first author, Dr. Helen Freeman, and that none of the …

Eight adult pairs of snow leopards (Panthera uncia) were observed for one to three years in the months December through March to determine the species' social and reproductive characteristics in captivity. To statistically examine the occurrence of behaviors as a function of estrus, the observation weeks were divided into three time blocks: before estrus, estrus, and after estrus. Using percentage of scan samples as an estimate of time spent in various behaviors, 16 behaviors and combined behavior categories were examined for (1) behaviors that differentiated successfully from unsuccessfully breeding pairs, (2) sex differences in behavior, (3) significant correlations between pair members, and (4) behaviors that showed time block effects. The rationale for identifying a behavioral profile of successful breeders in snow leopards was to aid zoos in their captive management programs by increasing their knowledge of the social behavior of this species. By finding correlates to breeding success, informed decisions on whether to change partners after a certain period of time, how to group the cats, and the optimum strategy for a survival plan can be made.

(1978). Education as a Socio‐Practical Field: The Restructuring of Educational Theory. Educational Philosophy and Theory: Vol. 10, No. 2, pp. 1-25.

(1980). Can Dewey Be Marx's Educational‐Philosophical Representative? Educational Philosophy and Theory: Vol. 12, No. 2, pp. 21-35.

(This is the first of two articles by John Clark and Helen Freeman, the second of which will appear in the journal's next issue, Vol. 3, No. 2, Summer 1979. Replies by Michael Young, Richard Pring, John White, and Graham Dawson will be published subsequently. Editor).

(1979). Egoism, ‘Morality’ and Irrationality – A Rejoinder to Harvey Siegel1. Educational Philosophy and Theory: Vol. 11, No. 1, pp. 51-61.

* Paper presented at the Tenth Annual Conference of the Philosophy of Education Society of A'asia, Brisbane, August 1979. It was submitted to Discourse by Helen Freeman prior to her tragic death. Permission to proceed with publication was subsequently authorised by Helen's co‐author.

This chapter discusses traditions of epistemology in educational philosophy and theory, which they as objectivist and constructivist. The emphasis is on the impossibility of an epistemological separation between the enquirer and the object of enquiry. On the early constructivist views of knowledge, there can be a very large number of alternative constructions of reality. If people create their own “realities”, then within the limits imposed by their own physiology and the world, they can re-create them differently through the use of alternative conceptual schemes. We live in a society in which science has high status as knowledge, on a positivist conception of science which prevails amongst the community as a whole. The claims of empirical science to be the only non-tautological knowledge possible and thus of special status rests on the radical separation of fact from value and the possibility of both neutrality and the elimination of “subjectivity” from scientific enquiry.

(Cell Metabolism 3, 35–45, January 2006)This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This paper is being retracted because of concerns with Figures 2B and S3. In Figure S3, the SDS-PAGE gel image had molecular weight markers added from another autoradiograph and additional nonspecific bands obscured or removed. In the top panel of Figure 2, an actin Western blot was used instead of a GCK Western blot. This matter was investigated by the Medical Research Council (UK) under their Scientific Misconduct Policy and Procedures, and scientific misconduct pertaining to the issues described here against the first author Helen Freeman was found. Repetition of these experiments by other group members gave identical results to those shown in the paper. Nevertheless, although we feel that the scientific conclusions of the paper (that loss of NNT impairs insulin secretion and impairs glucose tolerance in C57BL/6J mice) still stand, given the conclusion of scientific misconduct against the first author, the authors think the most responsible course is to retract the paper. The authors sincerely apologize for the inconvenience caused by this retraction.