MAP Kinase Modules: Many Roads Home

AbstractAll known MAP kinase cascades have a simple three tier linear architecture; yet despite their diverse range of inputs, they provide exquisitely precise and sensitive responses. Recent studies have shown that differential use of pathway components enhances pathway specificity, facilitates signal integration and confers output selectivity

TGF-β Regulation by Emilin1: New Links in the Etiology of Hypertension

Hypertension is a complex disease influenced by multiple genetic and environmental factors. The TGF-β signaling pathway has a long recognized role in blood pressure homeostasis. In this issue of Cell, Zacchigna et al. (2006) report that the secreted protein Emilin1 is a negative regulator of TGF-β signaling. Emilin1 knockout mice display elevated blood pressure due to increased TGF-β signaling in the vasculature

Starvation activates MAP kinase through the muscarinic acetylcholine pathway in Caenorhabditis elegans pharynx

SummaryStarvation activates MAPK in the pharyngeal muscles of C. elegans through a muscarinic acetylcholine receptor, Gqα, and nPKC as shown by the following results: (1) Starvation causes phosphorylation of MAPK in pharyngeal muscle. (2) In a sensitized genetic background in which Gqα signaling cannot be downregulated, activation of the pathway by a muscarinic agonist causes lethal changes in pharyngeal muscle function. Starvation has identical effects. (3) A muscarinic antagonist blocks the effects of starvation on sensitized muscle. (4) Mutations and drugs that block any step of signaling from the muscarinic receptor to MAPK also block the effects of starvation on sensitized muscle. (5) Overexpression of MAPK in wild-type pharyngeal muscle mimics the effects of muscarinic agonist and of starvation on sensitized muscle. We suggest that, during starvation, the muscarinic pathway to MAPK is activated to change the pharyngeal muscle physiology to enhance ingestion of food when food becomes available

Whitworth Park Community Archaeology and History Project: An Evaluation Report for the Heritage Lottery Fund

The Whitworth Park Community Archaeology and History Project took place between 2011 and 2015. The project investigated the material, social and natural history of Whitworth Park through archaeological survey and excavation, archival research and oral history. At the same time it engaged present-day communities with Whitworth Park’s rich past and its contribution to their urban heritage. The results of the project contributed to a wide range of activities and outputs that promoted public understanding well beyond the original project brief. These included tours of the excavations and the park, open days, a project blog, a Live Tweet, an exhibition, a public leaflet, a park display board, three short films, a series of lectures and workshops, and a number of preliminary publications addressing popular, professional and academic audiences. The project touched the lives of numerous people in diverse ways, ranging from the intensive participation of c.50 volunteers in the excavations and post-excavation work, to workshops for various classes from 6 schools, to some 44.5k visitors to the exhibition, to approximately 3.5k blog visitors and approximately 44.5k twitter accounts. Collectively, the volunteers dedicated 252 days and 1763 hours to the project.The project has contributed a great deal to our knowledge and understanding of Whitworth Park, providing intimate insights into the everyday lives of those who used it in the past. It equipped volunteers with new heritage-based skills as well as generic skills in team-working, communication and public engagement. Most importantly, it provided a strong sense of camaraderie in the shared excitement of discovery. School workshops facilitated connections and comparisons between childhood past and present, and gave children ranging from primary schools to 6th form colleges a taste of the significance and excitement of history and archaeology. Diverse and rewarding partnerships were created and fostered, many of which will be sustained beyond the lifetime of the project. Above all, the project has made a contribution to the work of those who care for public parks – their heritage and their future – ranging from the Friends of Whitworth Park to the Heritage Lottery Fund and other national organisations

Targeting the use of reminders and notifications for uptake by populations (TURNUP): a systematic review and evidence synthesis.

Background: Missed appointments are an avoidable cost and a resource inefficiency that impact on the health of the patient and treatment outcomes. Health-care services are increasingly utilising reminder systems to counter these negative effects. Objectives: This project explores the differential effect of reminder systems for different segments of the population for improving attendance, cancellation and rescheduling of appointments. Design: Three inter-related reviews of quantitative and qualitative evidence relating to theoretical explanations for appointment behaviour (review 1), the effectiveness of different approaches to reminding patients to attend health service appointments (review 2) and factors likely to influence non-attendance (review 3). Data sources: Database searches were conducted on Allied and Complementary Medicine, Cumulative Index to Nursing and Allied Health Literature Plus with Full Text, The Cochrane Library, EMBASE (via NHS Evidence from 1 January 2000 to January/February 2012), Health Management Information Consortium database, Institute of Electrical and Electronics Engineers Xplore, The King’s Fund Library Catalogue, Maternity and Infant Care, MEDLINE, Physiotherapy Evidence Database, PsycINFO, SPORTDiscus and Web of Science from 1 January 2000 to January/February 2012. Supplementary screening of references of included studies was conducted to identify additional potentially relevant studies. Conceptual papers were identified for review 1, randomised controlled trials (RCTs) and systematic reviews for review 2 and a range of quantitative and qualitative research designs for review 3. Methods: We conducted three inter-related reviews of quantitative and qualitative evidence, involving a review of conceptual frameworks of reminder systems and adherence behaviours, a review of the reminder effectiveness literature and a review informed by realist principles to explain the contexts and mechanisms that explain reminder effectiveness. A preliminary conceptual framework was developed to show how reminder systems work, for whom they work and in which circumstances. Six themes emerged that potentially influence the effectiveness of the reminder or whether or not patients would attend their appointment, namely the reminder–patient interaction, reminder accessibility, health-care settings, wider social issues, cancellation and rebookings, and distal/proxy attributes. Standardised review methods were used to investigate the effectiveness of reminders to promote attendance, cancellation or rebooking across all outpatient settings. Finally, a review informed by realist principles was undertaken, using the conceptualframework to explain the context and mechanisms that influence how reminders support attendance, cancellation and rebooking. Results: A total of 466 papers relating to 463 studies were identified for reviews 2 and 3. Findings from 31 RCTs and 11 separate systematic reviews (review 2 only) revealed that reminder systems are consistently effective at reducing non-attendance at appointments, regardless of health-care setting or patient subgroups. Simple reminders that provide details of timing and location of appointments are effective for increasing attendance at appointments. Reminders that provide additional information over and above the date, time and location of the appointment (‘reminder plus’) may be more effective than simple reminders at reducing non-attendance and may be particularly useful for first appointments and screening appointments; simple reminders may be appropriate thereafter for most patients the majority of the time. There was strong evidence that the timing of reminders, between 1 and 7 days prior to the appointment, has no effect on attendance; substantial numbers of patients do not receive their reminder; reminders promote cancellation of appointments; inadequate structural factors prevent patients from cancelling appointments; and few studies investigated factors that influence the effectiveness of reminder systems for population subgroups. Limitations: Generally speaking, the systematic review method seeks to provide a precise answer to a tightly focused question, for which there is a high degree of homogeneity within the studies. A wide range of population types, intervention, comparison and outcomes is included within the RCTs we identified. However, use of this wider approach offers greater analytical capability in terms of understanding contextual and mechanistic factors that would not have been evident in a more narrowly focused review and increases confidence that the findings will have relevance in a wide range of service settings. Conclusions: Simple reminders or ‘reminder plus’ should be sent to all patients in the absence of any clear contraindication. Other reminder alternatives may be relevant for key groups of patients: those from a deprived background, ethnic minorities, substance abusers and those with comorbidities and/or illnesses. We are developing a practice guideline that may help managers to further tailor their reminder systems for their service and client groups. We recommend future research activities in three main areas. First, more studies should routinely consider the potential for differential effects of reminder systems between patient groups in order to identify any inequalities and remedies. Second, ‘reminder plus’ systems appear promising, but there is a need for further research to understand how they influence attendance behaviour. Third, further research is required to identify strategies to ‘optimise’ reminder systems and compare performance with current approaches

Appointment reminder systems are effective but not optimal: results of a systematic review and evidence synthesis employing realist principles

Missed appointments are an avoidable cost and resource inefficiency which impact upon the health of the patient and treatment outcomes. Healthcare services are increasingly utilizing reminder systems to manage these negative effects. This study explores the effectiveness of reminder systems for promoting attendance, cancellations and rescheduling of appointments across all healthcare settings and for particular patient groups and the contextual factors which indicate that reminders are being employed sub-optimally. We used three inter-related reviews of quantitative and qualitative evidence. Firstly, using pre-existing models and theories, we developed a conceptual framework to inform our understanding of the Contexts and Mechanisms which influence reminder effectiveness. Secondly, we performed a review following Centre for Reviews & Dissemination (CRD) guidelines to investigate the effectiveness of different methods of reminding patients to attend health service appointments. Finally, to supplement the effectiveness information, we completed a review informed by realist principles to identify factors likely to influence non-attendance behaviors and the effectiveness of reminders. We found consistent evidence that all types of reminder systems are effective at improving appointment attendance across a range of health care settings and patient populations. Reminder systems may also increase cancellation and rescheduling of unwanted appointments. “Reminders plus”, which provide additional information beyond the reminder function, may be more effective than simple reminders at reducing non-attendance at appointments in particular circumstances. We identified six areas of inefficiency which indicate that reminder systems are being used sub-optimally. Unless otherwise indicated, all patients should receive a reminder to facilitate attendance at their healthcare appointment. The choice of reminder system should be tailored to the individual service. To optimize appointment and reminder systems, healthcare services need supportive administrative processes to enhance attendance, cancellation, rescheduling and re-allocation of appointments to other patients

Trans-disciplinary responses to climate change: lessons from rice-based systems in Asia

Climate change will continue to have a largely detrimental impact on the agricultural sector worldwide because of predicted rising temperatures, variable rainfall, and an increase in extreme weather events. Reduced crop yields will lead to higher food prices and increased hardship for low income populations, especially in urban areas. Action on climate change is one of the Sustainable Development Goals (SDG 13) and is linked to the Paris Climate Agreement. The research challenge posed by climate change is so complex that a trans-disciplinary response is required, one that brings together researchers, practitioners, and policy-makers in networks where the lines between “research” and “development” become deliberately blurred. Fostering such networks will require researchers, throughout the world, not only to work across disciplines but also to pursue new South–North and South–South partnerships incorporating policy-makers and practitioners. We use our diverse research experiences to describe the emergence of such networks, such as the Direct Seeded Rice Consortium (DSRC) in South and Southeast Asia, and to identify lessons on how to facilitate and strengthen the development of trans-disciplinary responses to climate change

Epigenetic dysregulation of naive CD4+ T-cell activation genes in childhood food allergy

Food allergy poses a significant clinical and public health burden affecting 2–10% of infants. Using integrated DNA methylation and transcriptomic profiling, we found that polyclonal activation of naive CD4+ T cells through the T cell receptor results in poorer lymphoproliferative responses in children with immunoglobulin E (IgE)-mediated food allergy. Reduced expression of cell cycle-related targets of the E2F and MYC transcription factor networks, and remodeling of DNA methylation at metabolic (RPTOR, PIK3D, MAPK1, FOXO1) and inflammatory genes (IL1R, IL18RAP, CD82) underpins this suboptimal response. Infants who fail to resolve food allergy in later childhood exhibit cumulative increases in epigenetic disruption at T cell activation genes and poorer lymphoproliferative responses compared to children who resolved food allergy. Our data indicate epigenetic dysregulation in the early stages of signal transduction through the T cell receptor complex, and likely reflects pathways modified by gene–environment interactions in food allergy