Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human β-amyloid

BACKGROUND: Interleukin 1 (IL-1) is a key mediator of immune responses in health and disease. Although classically the function of IL-1 has been studied in the systemic immune system, research in the past decade has revealed analogous roles in the CNS where the cytokine can contribute to the neuroinflammation and neuropathology seen in a number of neurodegenerative diseases. In Alzheimer's disease (AD), for example, pre-clinical and clinical studies have implicated IL-1 in the progression of a pathologic, glia-mediated pro-inflammatory state in the CNS. The glia-driven neuroinflammation can lead to neuronal damage, which, in turn, stimulates further glia activation, potentially propagating a detrimental cycle that contributes to progression of pathology. A prediction of this neuroinflammation hypothesis is that increased IL-1 signaling in vivo would correlate with increased severity of AD-relevant neuroinflammation and neuronal damage. METHODS: To test the hypothesis that increased IL-1 signaling predisposes animals to beta-amyloid (Aβ)-induced damage, we used IL-1 receptor antagonist Knock-Out (IL1raKO) and wild-type (WT) littermate mice in a model that involves intracerebroventricular infusion of human oligomeric Aβ1–42. This model mimics many features of AD, including robust neuroinflammation, Aβ plaques, synaptic damage and neuronal loss in the hippocampus. IL1raKO and WT mice were infused with Aβ for 28 days, sacrificed at 42 days, and hippocampal endpoints analyzed. RESULTS: IL1raKO mice showed increased vulnerability to Aβ-induced neuropathology relative to their WT counterparts. Specifically, IL1raKO mice exhibited increased mortality, enhanced microglial activation and neuroinflammation, and more pronounced loss of synaptic markers. Interestingly, Aβ-induced astrocyte responses were not significantly different between WT and IL1raKO mice, suggesting that enhanced IL-1 signaling predominately affects microglia. CONCLUSION: Our data are consistent with the neuroinflammation hypothesis whereby increased IL-1 signaling in AD enhances glia activation and leads to an augmented neuroinflammatory process that increases the severity of neuropathologic sequelae

Creative learning conversations: producing living dialogic spaces

publication-status: Publishedtypes: ArticleBackground ‘Creative learning conversations’, are methodological devices developed in two co-participative qualitative research projects exploring creativity and educational futures at the University of Exeter in England. Sources of evidence Framed by Critical Theory, the projects, one on dance education partnership, the other on student voice and transformation, sought to open space between creativity and performativity to initiate emancipatory educational change. This was undertaken over the course of five years in English primary and secondary schools, prioritising humanising, wise creativity (Chappell, 2008; Craft, 2008). Purpose This paper re-analyses data and methodological processes to characterise and theorise creative learning conversations in terms of social spatiality and dialogue. The characteristics are: partiality, emancipation, working from the ‘bottom up’, participation, debate and difference, openness to action, and embodied and verbalised idea exchange. Main argument This re-analysis theoretically adapts Bronfenbrenner’s (1979) ecological model to situate layered engagement. Utilising Lefebvre’s (1991) conceptualisation of Lived space and Bakhtin’s (1984) work on open-ended dialogue, the paper theorises creative learning conversations as producing living dialogic spaces. Conclusions Creative learning conversations are a way of contributing to change which moves us towards an education future fit for the twenty-first century. From a living dialogic space perspective a creative learning conversation is the ongoing process without forced closure of those in the roles of University academic, teachers, artists, students co-participatively researching and developing knowledge of their ‘lived space’ together. Given traditional lethargy in the educational system as a whole commitment to changing education for better futures demands active involvement in living dialogic space, where our humanity both emerges from and guides our shared learning

A novel p38α MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model

<p>Abstract</p> <p>Background</p> <p>An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38α MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (Aβ) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as <it>in vivo </it>research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38α MAPK is a potential <it>in vivo </it>target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes.</p> <p>Methods</p> <p>A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential <it>in vivo </it>bioavailability, metabolic stability, safety and brain uptake. Testing for <it>in vivo </it>efficacy used an AD-relevant mouse model.</p> <p>Results</p> <p>A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38α MAPK (MW01-2-069A-SRM) was developed. Oral administration of the compound at a low dose (2.5 mg/kg) resulted in attenuation of excessive proinflammatory cytokine production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficits.</p> <p>Conclusion</p> <p>The p38α MAPK pathway is quantitatively important in the Aβ-induced production of proinflammatory cytokines in hippocampus, and brain p38α MAPK is a viable molecular target for future development of potential disease-modifying therapeutics in AD and related neurodegenerative disorders.</p

Creative teaching and learning: towards a common discourse and practice

There has recently been a call for more pedagogic comparative research to counter the dominance of structural and policy led studies. At the same time there is also a necessity to provide alternative comparative research to that concerned with global standardising performance and performativity strategies. The research, on which this paper is based, fulfils both these aims by investigating creative teaching and learning in nine European countries at classroom level using ethnographic methods in a small number of sites for each partner. The research partners share a common discourse of pedagogy that we are calling creative teaching and learning, a common humanitarian discourse and the ethnographic methodology for the research was a strong framework to counter differing cultural approaches to research. The article analytically characterises some significant strategies used by teachers, the creative learning experienced and the meaning that the experiences had for the students involved. We conclude that this research has laid the basis for a common discourse for further research in a comparative approach that will investigate commonalities to build an understanding of international creative pedagogy and investigate differences to enhance the conceptualisation of it

Sarm1 knockout prevents type 1 diabetic bone disease in females independent of neuropathy

Patients with diabetes have a high risk of developing skeletal diseases accompanied by diabetic peripheral neuropathy (DPN). In this study, we isolated the role of DPN in skeletal disease with global and conditional knockout models of sterile-α and TIR-motif-containing protein-1 (Sarm1). SARM1, an NADase highly expressed in the nervous system, regulates axon degeneration upon a range of insults, including DPN. Global knockout of Sarm1 prevented DPN, but not skeletal disease, in male mice with type 1 diabetes (T1D). Female wild-type mice also developed diabetic bone disease but without DPN. Unexpectedly, global Sarm1 knockout completely protected female mice from T1D-associated bone suppression and skeletal fragility despite comparable muscle atrophy and hyperglycemia. Global Sarm1 knockout rescued bone health through sustained osteoblast function with abrogation of local oxidative stress responses. This was independent of the neural actions of SARM1, as beneficial effects on bone were lost with neural conditional Sarm1 knockout. This study demonstrates that the onset of skeletal disease occurs rapidly in both male and female mice with T1D completely independently of DPN. In addition, this reveals that clinical SARM1 inhibitors, currently being developed for treatment of neuropathy, may also have benefits for diabetic bone through actions outside of the nervous system

Fostering creativity with wisdom

This is a postprint of an article whose final and definitive form has been published in the Cambridge Journal of Education© 2006 Copyright University of Cambridge, Faculty of Education; Cambridge Journal of Education is available online at http://www.informaworld.comOver the past five years, creativity has become a focus of attention for policy-makers in education. However, the increased interest in creativity has occurred as if without reference to any value framework. This article suggests that in fact an invisible underpinning value framework has been provided by western individualism, in turn both supporting and driven by the globalized capitalist marketplace. What could this mean for nurturing creativity with wisdom in schools? Working from the stance that wisdom involves making thoughtful, well-informed and appropriate judgments leading to sound courses of action with regard to the consequences, this paper discusses some significant objections to a market-driven model of creativity in education, discusses a possible framework for understanding creativity in a way which emphasizes responsibility as well as rights to expression and proposes wisdom as a necessary element of pedagogy

NUScon: a community-driven platform for quantitative evaluation of nonuniform sampling in NMR

Although the concepts of nonuniform sampling (NUS) and non-Fourier spectral reconstruction in multidimensional NMR began to emerge 4 decades ago (Bodenhausen and Ernst, 1981; Barna and Laue, 1987), it is only relatively recently that NUS has become more commonplace. Advantages of NUS include the ability to tailor experiments to reduce data collection time and to improve spectral quality, whether through detection of closely spaced peaks (i.e., “resolution”) or peaks of weak intensity (i.e., “sensitivity”). Wider adoption of these methods is the result of improvements in computational performance, a growing abundance and flexibility of software, support from NMR spectrometer vendors, and the increased data sampling demands imposed by higher magnetic fields. However, the identification of best practices still remains a significant and unmet challenge. Unlike the discrete Fourier transform, non-Fourier methods used to reconstruct spectra from NUS data are nonlinear, depend on the complexity and nature of the signals, and lack quantitative or formal theory describing their performance. Seemingly subtle algorithmic differences may lead to significant variabilities in spectral qualities and artifacts. A community-based critical assessment of NUS challenge problems has been initiated, called the “Nonuniform Sampling Contest” (NUScon), with the objective of determining best practices for processing and analyzing NUS experiments. We address this objective by constructing challenges from NMR experiments that we inject with synthetic signals, and we process these challenges using workflows submitted by the community. In the initial rounds of NUScon our aim is to establish objective criteria for evaluating the quality of spectral reconstructions. We present here a software package for performing the quantitative analyses, and we present the results from the first two rounds of NUScon. We discuss the challenges that remain and present a roadmap for continued community-driven development with the ultimate aim of providing best practices in this rapidly evolving field. The NUScon software package and all data from evaluating the challenge problems are hosted on the NMRbox platform

Toward Defining the Preclinical Stages of Alzheimer's Disease: Recommendations from the National Institute on Aging-Alzheimer's Association Workgroups on Diagnostic Guidelines for Alzheimer's Disease

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious

An affinity matured minibody for PET imaging of prostate stem cell antigen (PSCA)-expressing tumors

PurposeProstate stem cell antigen (PSCA), a cell surface glycoprotein expressed in normal human prostate and bladder, is over-expressed in the majority of localized prostate cancer and most bone metastases. We have previously shown that the hu1G8 minibody, a humanized anti-PSCA antibody fragment (single-chain Fv-C(H)3 dimer, 80 kDa), can localize specifically and image PSCA-expressing xenografts at 21 h post-injection. However, the humanization and antibody fragment reformatting decreased its apparent affinity. Here, we sought to evaluate PET imaging contrast with affinity matured minibodies.MethodsYeast scFv display, involving four rounds of selection, was used to generate the three affinity matured antibody fragments (A2, A11, and C5) that were reformatted into minibodies. These three affinity matured anti-PSCA minibodies were characterized in vitro, and following radiolabeling with (124)I were evaluated in vivo for microPET imaging of PSCA-expressing tumors.ResultsThe A2, A11, and C5 minibody variants all demonstrated improved affinity compared to the parental (P) minibody and were ranked as follows: A2 &gt; A11 &gt; C5 &gt; P. The (124)I-labeled A11 minibody demonstrated higher immunoreactivity than the parental minibody and also achieved the best microPET imaging contrast in two xenograft models, LAPC-9 (prostate cancer) and Capan-1 (pancreatic cancer), when evaluated in vivo.ConclusionOf the affinity variant minibodies tested, the A11 minibody that ranked second in affinity was selected as the best immunoPET tracer to image PSCA-expressing xenografts. This candidate is currently under development for evaluation in a pilot clinical imaging study

Creativity in primary level dance education: moving beyond assumption

This is a preprint of an article whose final and definitive form has been published in Research in Dance Education © 2007 Copyright Taylor & Francis; Research in Dance Education is available online at http://www.informaworld.com.This paper represents the final layer of analysis carried out in a study investigating the conceptions of and approaches to creativity of three expert specialist dance teachers within late primary age dance education in the UK. This research journeyed through a number of phases culminating in an analysis of the pedagogical dilemmas encountered by the three teachers in their specific situations in relation to creativity in dance education in the current UK climate. This article details the dilemmas and their solutions, articulating the issues and tensions which, within the kinds of situation studied, might be endangering meaningful creative experiences for learners in dance education. Within a theoretical framework, the findings map the terrain for this particular group of teachers, and offer 'images of the possible' for other dance and education professionals. The paper culminates by offering suggestions of future directions for intertwining research and developing practice in creativity in dance and education research in this area.This research was initially supported by a Research Studentship from the LABAN Graduate School and subsequently by a Post Graduate Award from the Arts and Humanities Research Council