RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI

Electronic medical records in paediatric ophthalmology: a study of potential users and uses to inform design

Electronic medical records are at the core of an advancing movement toward information-driven healthcare. By enhancing abilities to capture, store, and analyse vast amounts of health data, the routine use of electronic medical records is advocated as a means to improve the efficiency and quality of care provision, advance population health, empower patients, and reduce healthcare costs. However, the delivery of any benefits is threatened by a failure to understand the unique care environments of different clinical specialties, and to appropriately customise system design. This has prompted a move to the user-centred design process of health information technology. Paediatric ophthalmology is a unique field that faces particular challenges in electronic medical record adoption. As with other ophthalmic specialties, the heavy use of imaging and diagrammatic documentation is difficult to replicate electronically. As is the flexibility required to meet the demands incurred by the varying ages, developmental stages, and visual needs of each patient, reflecting a unique interface between the ophthalmic and paediatric requirements. The consideration of such requirements is essential throughout the user-centred design of effective health information technology systems. However, paucity in the evidence base surrounding electronic medical record design methodologies and system usage hinders technological development and application within paediatric ophthalmology. This research was centred on a user-centred design process, to provide an understanding of the users of electronic medical records in paediatric ophthalmology, and their requirements. Taking a mixed methods approach, this research initially explored the landscape of medical record use – gathering user- centred requirements – and concluded with the development and testing of three prototype data collection forms, for specific use cases within paediatric ophthalmology. Overall, this work articulates the specific challenges and requirements in this area, and provides the foundation for future design and adoption strategies of electronic medical record systems within paediatric ophthalmology

The relationship between school climate and mental and emotional wellbeing over the transition from primary to secondary school

Background: School climate has often been described as the “quality and character of school life”, including both social and physical aspects of the school, that can positively promote behaviour, school achievement, and the social and emotional development of students. Methods: The current study examined the relationship between students’ mental and emotional wellbeing and factors pertaining to school climate, focussing on the domains of safety, social relationships and school connectedness, during the last year of their primary schooling (age 11–12 years) and their first 2 years of secondary school. Data was collected using a self-completion questionnaire, four times over 3 years from 1800 students’ aged 11–14 years. Multilevel modelling was used to determine the strongest school climate predictor of students’ mental and emotional wellbeing at each time point. Results: In the last year of primary school, peer support was the strongest protective predictor of wellbeing, while feeling less connected and less safe at school predicted mental wellbeing. Feeling safe at school was the strongest protective factor for student wellbeing in the first year of secondary school. In the second year of secondary school, peer support was the strongest protective factor for mental wellbeing, while feeling safe at school, feeling connected to school and having support from peers were predictive of emotional wellbeing. Conclusions: School climate factors of feeling safe at school, feeling connected to school, and peer support are all protective of mental and emotional wellbeing over the transition period while connectedness to teachers is protective of emotional wellbeing. Primary school appears to be an important time to establish quality connections to peers who have a powerful role in providing support for one another before the transition to secondary school. However, school policies and practices promoting safety and encouraging and enabling connectedness are important during the first years of secondary school. Recommendations for effective school policy and practice in both primary and sec- ondary schools to help enhance the mental and emotional wellbeing of adolescents are discussed

Vortices in polariton OPO superfluids

This chapter reviews the occurrence of quantised vortices in polariton fluids, primarily when polaritons are driven in the optical parametric oscillator (OPO) regime. We first review the OPO physics, together with both its analytical and numerical modelling, the latter being necessary for the description of finite size systems. Pattern formation is typical in systems driven away from equilibrium. Similarly, we find that uniform OPO solutions can be unstable to the spontaneous formation of quantised vortices. However, metastable vortices can only be injected externally into an otherwise stable symmetric state, and their persistence is due to the OPO superfluid properties. We discuss how the currents charactering an OPO play a crucial role in the occurrence and dynamics of both metastable and spontaneous vortices.Comment: 40 pages, 16 figure

Continuation for thin film hydrodynamics and related scalar problems

This chapter illustrates how to apply continuation techniques in the analysis of a particular class of nonlinear kinetic equations that describe the time evolution through transport equations for a single scalar field like a densities or interface profiles of various types. We first systematically introduce these equations as gradient dynamics combining mass-conserving and nonmass-conserving fluxes followed by a discussion of nonvariational amendmends and a brief introduction to their analysis by numerical continuation. The approach is first applied to a number of common examples of variational equations, namely, Allen-Cahn- and Cahn-Hilliard-type equations including certain thin-film equations for partially wetting liquids on homogeneous and heterogeneous substrates as well as Swift-Hohenberg and Phase-Field-Crystal equations. Second we consider nonvariational examples as the Kuramoto-Sivashinsky equation, convective Allen-Cahn and Cahn-Hilliard equations and thin-film equations describing stationary sliding drops and a transversal front instability in a dip-coating. Through the different examples we illustrate how to employ the numerical tools provided by the packages auto07p and pde2path to determine steady, stationary and time-periodic solutions in one and two dimensions and the resulting bifurcation diagrams. The incorporation of boundary conditions and integral side conditions is also discussed as well as problem-specific implementation issues

Color-Changing Device to Improve Adherence to Foley Catheter Replacement Protocols and Reduce Urinary Tract Infection Frequency

Background: Foley catheter-associated UTI’s (CAUTI’s) represent a driving cause of cystitis, bacteremia and sepsis in the hospital setting. Accordingly, the CDC has identified prolonged indwelling time as the foremost risk factor for CAUTI’s. However, the fundamental design of the Foley has remained unchanged for over eighty years. Hospital-specific protocols do currently exist for the removal of infection-prone catheters; however, in practice it remains commonplace for catheters to be ignored, increasing the risk of life-threatening infection. Our design process addressed this by creating a color-changing alarm device that would alert providers when a catheter has been left in beyond protocol, is at risk for infection, and should be assessed for removal. Methods: In-depth interviewing with the goal of collecting end-user feedback was conducted during our design process. Working with an infectious disease case manager, two physicians (urology and EM), and the CAUTI nursing chair, we targeted two primary aspects of CAUTI use: procedures currently used to determine infection risk of indwelling catheters, and potential strategies for alerting and preventing CAUTI’s. “Design Thinking” framework allowed us to incorporate stakeholder feedback, iterate ideas for, and prototype our color-changing alarm device. Results: Interviews suggest that despite current protocols, providers continue to leave catheters indwelling beyond suggested time limits. End-user feedback also indicated an urgent need for an innovative strategy to assist in the recognition of infection-prone catheters and to limit CAUTI’s. Conclusions: Currently, the color-indicator alarm system is within the prototyping phase of the iterative design process. We will incorporate end-user expert feedback (such as the five-to-eight day “critical window” suggested by our experts for catheter assessment and removal) into the product design. Future hospital trials will test whether the device improves the recognition of infectionprone catheters, effectively notifies providers of catheters left indwelling, and decreases the incidence of CAUTI’s

Biodiversity in a changing climate: a synthesis of current and projected trends in the US

This paper provides a synthesis of the recent literature describing how global biodiversity is being affected by climate change and is projected to respond in the future. Current studies reinforce earlier findings of major climate-change-related impacts on biological systems and document new, more subtle after-effects. For example, many species are shifting their distributions and phenologies at faster rates than were recorded just a few years ago; however, responses are not uniform across species. Shifts have been idiosyncratic and in some cases counterintuitive, promoting new community compositions and altering biotic interactions. Although genetic diversity enhances species\u27 potential to respond to variable conditions, climate change may outpace intrinsic adaptive capacities and increase the relative vulnerabilities of many organisms. Developing effective adaptation strategies for biodiversity conservation will not only require flexible decision-making and management approaches that account for uncertainties in climate projections and ecological responses but will also necessitate coordinated monitoring efforts

Safeguarding pollinators and their values to human well-being

Wild and managed pollinators provide a wide range of benefits to society in terms of contributions to food security, farmer and beekeeper livelihoods, social and cultural values, as well as the maintenance of wider biodiversity and ecosystem stability. Pollinators face numerous threats, including changes in land-use and management intensity, climate change, pesticides and genetically modified crops, pollinator management and pathogens, and invasive alien species. There are well-documented declines in some wild and managed pollinators in several regions of the world. However, many effective policy and management responses can be implemented to safeguard pollinators and sustain pollination services

An Agent-Based Model of a Hepatic Inflammatory Response to Salmonella: A Computational Study under a Large Set of Experimental Data

Citation: Shi, Z. Z., Chapes, S. K., Ben-Arieh, D., & Wu, C. H. (2016). An Agent-Based Model of a Hepatic Inflammatory Response to Salmonella: A Computational Study under a Large Set of Experimental Data. Plos One, 11(8), 39. doi:10.1371/journal.pone.0161131We present an agent-based model (ABM) to simulate a hepatic inflammatory response (HIR) in a mouse infected by Salmonella that sometimes progressed to problematic proportions, known as "sepsis". Based on over 200 published studies, this ABM describes interactions among 21 cells or cytokines and incorporates 226 experimental data sets and/or data estimates from those reports to simulate a mouse HIR in silico. Our simulated results reproduced dynamic patterns of HIR reported in the literature. As shown in vivo, our model also demonstrated that sepsis was highly related to the initial Salmonella dose and the presence of components of the adaptive immune system. We determined that high mobility group box-1, C-reactive protein, and the interleukin-10: tumor necrosis factor-a ratio, and CD4+ T cell: CD8+ T cell ratio, all recognized as biomarkers during HIR, significantly correlated with outcomes of HIR. During therapy-directed silico simulations, our results demonstrated that anti-agent intervention impacted the survival rates of septic individuals in a time-dependent manner. By specifying the infected species, source of infection, and site of infection, this ABM enabled us to reproduce the kinetics of several essential indicators during a HIR, observe distinct dynamic patterns that are manifested during HIR, and allowed us to test proposed therapy-directed treatments. Although limitation still exists, this ABM is a step forward because it links underlying biological processes to computational simulation and was validated through a series of comparisons between the simulated results and experimental studies