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SummaryNeutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. We identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies reveal increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. These findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.

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.

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.

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.