Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model

<b>Background and Purpose</b><p></p> cAMP and pharmacological inhibition of PDE4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury (SCI). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE4-specific inhibitor rolipram and other modulators of downstream signalling effectors.<p></p> <b>Experimental Approach</b><p></p> Rat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE4-specific inhibitor rolipram, Epac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR.<p></p> <b>Key Results</b><p></p> Inhibition of the high-affinity rolipram-binding state (HARBS), rather than the low-affinity rolipram binding state (LARBS) PDE4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE4.<p></p> <b>Conclusions and Implications</b><p></p> PDE4 inhibitors targeted at the HARBS conformer or Epac agonists may provide promising novel targets for the treatment of SCI. Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI. These findings need to be confirmed in vivo

Temporal dynamics of hydrological threshold events

International audienceThe episodic nature of hydrological flows such as surface runoff and preferential flow is a result of the nonlinearity of their triggering and the intermittency of rainfall. In this paper we examine the temporal dynamics of threshold processes that are triggered by either an infiltration excess (IE) mechanism when rainfall intensity exceeds a specified threshold value, or a saturation excess (SE) mechanism governed by a storage threshold. We analytically derive probabilistic measures of the time between successive events in each case, and in the case of the SE triggering, we relate the statistics of the time between events to the statistics of storage and the underlying water balance. In the case of the IE mechanism, the temporal dynamics of flow events is shown to be simply scaled statistics of rainfall timing. In the case of the SE mechanism the time between events becomes structured. With increasing climate aridity the mean and the variance of the time between SE events increases but temporal clustering, as measured by the coefficient of variation (CV) of the inter-event time, reaches a maximum in deep stores when the climatic aridity index equals 1. In very humid and also very arid climates, the temporal clustering disappears, and the pattern of triggering is similar to that seen for the IE mechanism. In addition we show that the mean and variance of the magnitude of SE events decreases but the CV increases with increasing aridity. The CV of inter-event times is found to be approximately equal to the CV of the magnitude of SE events per storm only in very humid climates with the CV of event magnitude tending to be much larger than the CV of inter-event times in arid climates. In comparison to storage the maximum temporal clustering was found to be associated with a maximum in the variance of soil moisture. The CV of the time till the first saturation excess event was found to be greatest when the initial storage was at the threshold

Key features of palliative care service delivery to Indigenous peoples in Australia, New Zealand, Canada and the United States: A comprehensive review

Background: Indigenous peoples in developed countries have reduced life expectancies, particularly from chronic diseases. The lack of access to and take up of palliative care services of Indigenous peoples is an ongoing concern. Objectives: To examine and learn from published studies on provision of culturally safe palliative care service delivery to Indigenous people in Australia, New Zealand (NZ), Canada and the United States of America (USA); and to compare Indigenous peoples’ preferences, needs, opportunities and barriers to palliative care. Methods: A comprehensive search of multiple databases was undertaken. Articles were included if they were published in English from 2000 onwards and related to palliative care service delivery for Indigenous populations; papers could use quantitative or qualitative approaches. Common themes were identified using thematic synthesis. Studies were evaluated using Daly’s hierarchy of evidence-for-practice in qualitative research. Results: Of 522 articles screened, 39 were eligible for inclusion. Despite diversity in Indigenous peoples’ experiences across countries, some commonalities were noted in the preferences for palliative care of Indigenous people: to die close to or at home; involvement of family; and the integration of cultural practices. Barriers identified included inaccessibility, affordability, lack of awareness of services, perceptions of palliative care, and inappropriate services. Identified models attempted to address these gaps by adopting the following strategies: community engagement and ownership; flexibility in approach; continuing education and training; a whole-of-service approach; and local partnerships among multiple agencies. Better engagement with Indigenous clients, an increase in number of palliative care patients, improved outcomes, and understanding about palliative care by patients and their families were identified as positive achievements. Conclusions: The results provide a comprehensive overview of identified effective practices with regards to palliative care delivered to Indigenous populations to guide future program developments in this field. Further research is required to explore the palliative care needs and experiences of Indigenous people living in urban areas

Low-energy electron diffraction study of potassium adsorbed on single-crystal graphite and highly oriented pyrolytic graphite

Potassium adsorption on graphite has been a model system for the understanding of the interaction of alkali metals with surfaces. The geometries of the s232d structure of potassium on both single-crystal graphite (SCG) and highly oriented pyrolytic graphite (HOPG) were investigated for various preparation conditions for graphite temperatures between 55 and 140 K. In all cases, the geometry was found to consist of K atoms in the hollow sites on top of the surface. The K-graphite average perpendicular spacing is 2.79±0.03 Å, corresponding to an average C-K distance of 3.13±0.03 Å, and the spacing between graphite planes is consistent with the bulk spacing of 3.35 Å. No evidence was observed for a sublayer of potassium. The results of dynamical LEED studies for the clean SCG and HOPG surfaces indicate that the surface structures of both are consistent with the truncated bulk structure of graphite

Protecting expatriates in hostile environments: institutional forces influencing the safety and security practices of internationally active organisations

© 2017, © 2017 Informa UK Limited, trading as Taylor & Francis Group. The operations of internationally active organisations continue to encroach on hostile locations that are vulnerable to the negative consequences of crises such as political upheaval, terrorist attacks or natural disasters. Yet research into how firms ensure the physical and psychological safety and security of international staff in these locations is limited. This article reports an empirical study exploring the expatriate safety and security practices of 28 internationally active organisations from three industries that commonly operate in hostile environments. We unveil starkly different approaches across the three industries, and label these approaches ‘regulatory’ (mining and resources), ‘informal mentoring’ (news media) and ‘empowering’ (international aid and development). We use institutional theory to propose that these configurations reflect legitimacy-seeking choices that these organisations make in response to the various institutional environments that affect each sector. Our results provide a platform for initial theory building into the interrelated elements of organisations’ safety and security practices, and the institutional factors that shape the design of these

Criminal sentencing by preferred numbers

Criminal sentencing is a complex cognitive activity often performed by the unaided mind under suboptimal conditions. As such, sentencers may not behave according to policy, guidelines and training. We analyzed the distribution of sentences meted out in one year in two different jurisdictions (i.e., England and Wales, and New South Wales, Australia). We reveal that sentencers prefer certain numbers when meting out sentence lengths (in custody and community service) and amounts (for fines/compensation). These ‘common doses’ accounted for over 90% of sentences in each jurisdiction. The size of these doses increased as sentences became more severe, and doses followed a logarithmic pattern. These findings are compatible with psychological research on preferred numbers and are reminiscent of Weber’s and Fechner’s laws. Our findings run contrary to arguments against efforts to reduce judicial discretion, and potentially undermine the notion of individualized justice, as well as raise questions about the (cost) effectiveness of sentencing

Rethinking the employability of international graduate migrants: reflections on the experiences of Zimbabweans with degrees from England

The last decade has seen the rise of literatures that have focused on the rapid expansion of the numbers of international students in higher education globally and the growing policy discourse around improving graduate employability. However, both, inevitably, have limitations. Together, they tend to homogenise international learners and see them narrowly as simply economic actors. More recently, however, there have been signs of important new developments in both literatures, drawing on interactive employability and capability accounts that stress both agency and structure in more satisfactory ways. We seek to further the development of an account that bridges the new wave of student mobility research and the capability-employability account. In doing so, we offer two further elements to the literature. First, we aim to bridge the gap between international higher education accounts and those of migration and diasporic studies. Second, we deliberately focus on a group that is marginal to the mainstream discourse but who are migrants that have engaged in international higher education in order to improve their labour market prospects, amongst other motivations. We do this through examining the stories of five Zimbabweans who embarked on additional higher educational studies in England after migrating to the country. Through this unique approach, we offer an important new perspective on how the debates on international higher education, employability and migration can be taken forward through closer articulation between these accounts

Developing interventions to address sexuality after stroke: Findings from a four-panel modified delphi study

© 2019 Foundation of Rehabilitation Information. Background: Although stroke has a profound impact on sexuality there are limited evidence-based interventions to support rehabilitation professionals in this area. The aim of the current research was to prioritize content areas and approaches to sexual rehabilitation from the perspective of stroke survivors, their partners, stroke rehabilitation clinicians and researchers. Methods: A 2-step online Delphi method was used to prioritize the content of, and approaches to, sexual rehabilitation with stroke survivors, their partners, stroke rehabilitation clinicians and researchers. Results: Stroke survivors (n=30), their partners (n=18), clinicians and researchers in stroke rehabilitation (n=45) completed at least 1 of 2 investigator-developed surveys. Participants prioritized 18 core content areas for inclusion in sexual rehabilitation following stroke with a high degree of consensus. Another 27 content areas were considered moderately important. There was strong consensus that sexual rehabilitation should be offered in the subacute and chronic phases of stroke recovery. Participants would prefer health professionals to deliver the intervention face-to-face. Conclusion: This study presents opinions from stroke survivors, partners of stroke survivors, clinicians and researchers. The information about content, timing and mode of delivery will be used to develop and evaluate a comprehensive sexuality rehabilitation programme

The surface science of quasicrystals

The surfaces of quasicrystals have been extensively studied since about 1990. In this paper we review work on the structure and morphology of clean surfaces, and their electronic and phonon structure. We also describe progress in adsorption and epitaxy studies. The paper is illustrated throughout with examples from the literature. We offer some reflections on the wider impact of this body of work and anticipate areas for future development. (Some figures in this article are in colour only in the electronic version

Stellar Populations of Luminous Evolved Galaxies at z~1.5

Observational evidence has been mounting over the past decade that at least some luminous (~2 L*) galaxies have formed nearly all of their stars within a short period of time only 1-2x10^9 years after the Big Bang. These are examples of the first major episodes of star formation in the Universe and provide insights into the formation of the earliest massive galaxies. We have examined in detail the stellar populations of six z~1.5 galaxies that appear to be passively evolving, using both ground and space-based photometry covering rest-frame UV to visible wavelengths. In addition, we have obtained medium-resolution spectroscopy for five of the six galaxies, covering the rest-frame UV portion of the spectrum. Spectral synthesis modeling for four of these galaxies favors a single burst of star formation more than 1 Gyr before the observed epoch. The other two exhibit slightly younger ages with a higher dust content and evidence for a small contribution from either recent star formation or active nuclei. The implied formation redshifts for the oldest of these sources are consistent with previous studies of passive galaxies at high redshift, and improved stellar modeling has shown these results to be quite robust. It now seems clear that any valid galaxy formation scenario must be able to account for these massive (2x10^11 M_sun) galaxies at very early times in the Universe.Comment: 10 pages, 3 figures (2 in color), accepted for publication in Ap