RACK(1) to the future - a historical perspective

Abstract This perspective summarises the first and long overdue RACK1 meeting held at the University of Limerick, Ireland, May 2013, in which RACK1's role in the immune system, the heart and the brain were discussed and its contribution to disease states such as cancer, cardiac hypertrophy and addiction were described. RACK1 is a scaffolding protein and a member of the WD repeat family of proteins. These proteins have a unique architectural assembly that facilitates protein anchoring and the stabilisation of protein activity. A large body of evidence is accumulating which is helping to define the versatile role of RACK1 in assembling and dismantling complex signaling pathways from the cell membrane to the nucleus in health and disease. In this commentary, we first provide a historical perspective on RACK1. We also address many of the pertinent and topical questions about this protein such as its role in transcription, epigenetics and translation, its cytoskeletal contribution and the merits of targeting RACK1 in disease. Historical perspective It has been 20 years since RACK1 was cloned as the first identified binding protein for Protein Kinase C (PKC), and the road the Mochly-Rosen group took toward its discovery was not trivial. The role of scaffolding proteins in the temporal and spatial regulation of signal transduction seems obvious today, however, this was not the case in the late 1980s when Prof. Daria Mochly-Rosen developed the hypothesis that anchoring/scaffolding proteins control the specificity of substrate phosphorylation and function of Protein Kinase C (PKC) isozymes. An alpha phage display library/overlay assay strategy was used to identify binding proteins that interact with active PKC isoforms. To this day Dr. Ron remembers when one gene product was identified and was termed RACK1 for Receptor for Activated C Kinase RACK1 as a scaffolding protein The conserved seven blade propeller structure of RACK1 facilitates the folding order into constituent propeller blades. These propeller blades are intrinsic to RACK1's protein binding capacity and allow RACK1 to function as a signaling hub RACK1: a scaffolding protein with a central role in transcription, epigenetics & translation RACK1 has a strong effect on transcription and translation by acting at critical points; principally the ribosomal small subunit and via nuclear translocation and regulation of chromatin and transcriptional complexes RACK1 and cytoskeletal proteins: a new frontier The cellular cytoskeleton, whose major components comprise of actin, microtubules and intermediate filaments, maintains cellular integrity and regulates multiple cellular functions including migration RACK1 as a potential therapeutic target As the number of binding partners and validated cellular functions for RACK1 has increased, so has its link with an array of disease states [38] are amongst the first describing beta-propeller/small molecule complexes. Interestingly, the report by Senisterra et al. Concluding comments There are, of course, numerous remaining questions that are of great interest. For example, how can one protein play such an important role in many and diverse biological functions? Is it possible that a number of RACK1 binding partners share common binding sites on RACK1? Is RACK1 function and/or expression levels regulated by posttranslational modifications such as phosphorylation, sumoylation and ubiquitination? Does RACK1 contribute to a large number of disease states and can RACK1 be used as a target for drug development? These are exciting times for RACK1 biologists. As more and more research areas converge on RACK1, we can expect answers to these questions to unfold. RACK1 biology would benefit greatly from detailed mechanistic mathematical modelling and quantitative experimentation to help us comprehend how RACK1 functions in systems biology, beyond its role as a scaffolding protein. We look forward to the next RACK1 conference, which we have no doubt will bring more exciting new data on the role of our favorite protein in cellular functions

DEAR project: Lunar dust surface interactions, risk and removal investigations

The DEAR project (Dusty Environment Application Research) investigates the interaction between lunar regolith and surfaces and components relevant for lunar exploration. Based on the TUBS regolith simulant which is representative in chemistry, size and shape properties to Moon soils to study the regolith transport, adhesion and strategies for cleaning. The regolith simulant will be applied to thermal, structural, optical sensor, sealing and other astronautic systems, providing input for requirements, justification and verification. The key applications are split in human space flight regolith investigations, wrinkled surface with random movement and hardware surfaces, flat material defined movement. The paper provides an overview of the DEAR project including a discussion of the first results, in particular vibration, shock and micro-vibration on regolith bearing surfaces. The investigation shall enable better understand the regolith layers interaction and the release mechanism, as well as potential cross contamination and cleaning strategies. The research is complemented by simulation of the regolith motion as parameter surface plasma interactions. The project is funded and supported by the European Space Agency (ESA). DEAR specifically addresses the development and testing of lunar dust removal strategies on optics, mechanisms and human space flight hardware (e.g., space suits). As the Moons regolith is known to be highly abrasive, electrically chargeable, and potentially chemically reactive, lunar dust might reduce the performance of hardware, such as cameras, thermal control surfaces and solar cells. The dust can cause malfunction on seals for on/off mechanisms or space suits. Of particular interest are risk assessment, avoidance, and cleaning techniques such as the use of electric fields to remove lunar dust from surfaces. Representative dust (e.g., regolith analogues of interesting landing sites) will be used in a dedicated test setup to evaluate risks and effects of lunar dust. We describe designs and methods developed by the DEAR consortium to deal with the regolith-related issues, in particular an electrode design to deflect regolith particles, cleaning of astronautical systems with CO2, design of a robotic arm for the testing within the DEAR chamber, regolith removal via shock, and regolith interaction with cleanroom textile

Back to the Future – In support of a renewed emphasis on generic agility training within sports-specific developmental pathways

Perhaps as a consequence of increased specialism in training and support, the focus on engendering and maintaining agility as a generic quality has diminished within many contemporary sports performance programmes. Reflecting this, we outline a rationale suggesting that such a decreased focus represents an oversight which may be detrimental to maximising the potential of performers. We present an evidence-based argument that both generic and specific elements of agility performance should be consistently emphasised within long-term performance-training programmes. We contend that prematurely early specialisation in athlete development models can diminish focus on generic movement skill development with a subsequent detriment in adult performance. Especially when this is coupled with poor primary physical education and limited movement experiences. More speculatively, we propose that generic agility can play a role in operationalising movement development through facilitating skill transfer: thereby enabling the learning of new skills, reduce incidence of injury and facilitating re-learning of old skills during rehabilitation and Return-to-Play processes

Reduced level of arousal and increased mortality in adult acute medical admissions: a systematic review and meta-analysis

Abstract Background Reduced level of arousal is commonly observed in medical admissions and may predict in-hospital mortality. Delirium and reduced level of arousal are closely related. We systematically reviewed and conducted a meta-analysis of studies in adult acute medical patients of the relationship between reduced level of arousal on admission and in-hospital mortality. Methods We conducted a systematic review (PROSPERO: CRD42016022048), searching MEDLINE and EMBASE. We included studies of adult patients admitted with acute medical illness with level of arousal assessed on admission and mortality rates reported. We performed meta-analysis using a random effects model. Results From 23,941 studies we included 21 with 14 included in the meta-analysis. Mean age range was 33.4 - 83.8 years. Studies considered unselected general medical admissions (8 studies, n=13,039) or specific medical conditions (13 studies, n=38,882). Methods of evaluating level of arousal varied. The prevalence of reduced level of arousal was 3.1%-76.9% (median 13.5%). Mortality rates were 1.7%-58% (median 15.9%). Reduced level of arousal was associated with higher in-hospital mortality (pooled OR 5.71; 95% CI 4.21-7.74; low quality evidence: high risk of bias, clinical heterogeneity and possible publication bias). Conclusions Reduced level of arousal on hospital admission may be a strong predictor of in-hospital mortality. Most evidence was of low quality. Reduced level of arousal is highly specific to delirium, better formal detection of hypoactive delirium and implementation of care pathways may improve outcomes. Future studies to assess the impact of interventions on in-hospital mortality should use validated assessments of both level of arousal and delirium

Warming response of peatland CO2 sink is sensitive to seasonality in warming trends

Peatlands have acted as net CO2 sinks over millennia, exerting a global climate cooling effect. Rapid warming at northern latitudes, where peatlands are abundant, can disturb their CO2 sink function. Here we show that sensitivity of peatland net CO2 exchange to warming changes in sign and magnitude across seasons, resulting in complex net CO2 sink responses. We use multiannual net CO2 exchange observations from 20 northern peatlands to show that warmer early summers are linked to increased net CO2 uptake, while warmer late summers lead to decreased net CO2 uptake. Thus, net CO2 sinks of peatlands in regions experiencing early summer warming, such as central Siberia, are more likely to persist under warmer climate conditions than are those in other regions. Our results will be useful to improve the design of future warming experiments and to better interpret large-scale trends in peatland net CO2 uptake over the coming few decades.Peatlands have historically acted as a carbon sink, but it is unclear how climate warming will affect this. The response of peatland carbon uptake to warming depends on the timing of summer warming; early warming leads to increased CO2 uptake and later warming to decreased uptake

Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: a sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis

The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2–5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pre-treatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs

Communication is key: a study of the development of communication key skills in China

Different countries offer alternative curricula around what might be designated language, literacy and/or communication. This paper focuses on the latter which has typically been associated with vocational education and often labelled a ‘key’ or ‘core’ skill that forms part of a wider set of life and employability skills. In recent years, as China has emerged as a global economy, education has been significant in its policy and development. This research explores staff and student responses to the introduction of a key skills communication course in three Chinese further education vocational colleges. The initiative was prompted by research in China which had suggested that communication is important not just for education (Ye and Li 2007) but also for employability, and that the ability to communicate effectively could be instrumental in individuals’ success and development (Tong and Zhong 2008). It explores what communication key skills might mean in a Chinese context and questions notions of transferability and of competence and performance in communication. It analyses how motivation could affect learner success and the relationship of pedagogy to curriculum and, finally, it considers how communication might be an element in the longer-term social and political development of critical literacies

Predicting mortality of residents at admission to nursing home: A longitudinal cohort study

<p>Abstract</p> <p>Background</p> <p>An increasing numbers of deaths occur in nursing homes. Knowledge of the course of development over the years in death rates and predictors of mortality is important for officials responsible for organizing care to be able to ensure that staff is knowledgeable in the areas of care needed. The aim of this study was to investigate the time from residents' admission to Icelandic nursing homes to death and the predictive power of demographic variables, health status (health stability, pain, depression and cognitive performance) and functional profile (ADL and social engagement) for 3-year mortality in yearly cohorts from 1996-2006.</p> <p>Methods</p> <p>The samples consisted of residents (N = 2206) admitted to nursing homes in Iceland in 1996-2006, who were assessed once at baseline with a Minimum Data Set (MDS) within 90 days of their admittance to the nursing home. The follow-up time for survival of each cohort was 36 months from admission. Based on Kaplan-Meier analysis (log rank test) and non-parametric correlation analyses (Spearman's rho), variables associated with survival time with a p-value < 0.05 were entered into a multivariate Cox regression model.</p> <p>Results</p> <p>The median survival time was 31 months, and no significant difference was detected in the mortality rate between cohorts. Age, gender (HR 1.52), place admitted from (HR 1.27), ADL functioning (HR 1.33-1.80), health stability (HR 1.61-16.12) and ability to engage in social activities (HR 1.51-1.65) were significant predictors of mortality. A total of 28.8% of residents died within a year, 43.4% within two years and 53.1% of the residents died within 3 years.</p> <p>Conclusion</p> <p>It is noteworthy that despite financial constraints, the mortality rate did not change over the study period. Health stability was a strong predictor of mortality, in addition to ADL performance. Considering these variables is thus valuable when deciding on the type of service an elderly person needs. The mortality rate showed that more than 50% died within 3 years, and almost a third of the residents may have needed palliative care within a year of admission. Considering the short survival time from admission, it seems relevant that staff is trained in providing palliative care as much as restorative care.</p

Remote sensing of annual terrestrial gross primary productivity from MODIS: an assessment using the FLUXNET La Thuile data set

Gross primary productivity (GPP) is the largest and most variable component of the global terrestrial carbon cycle. Repeatable and accurate monitoring of terrestrial GPP is therefore critical for quantifying dynamics in regional-to-global carbon budgets. Remote sensing provides high frequency observations of terrestrial ecosystems and is widely used to monitor and model spatiotemporal variability in ecosystem properties and processes that affect terrestrial GPP. We used data from the Moderate Resolution Imaging Spectroradiometer (MODIS) and FLUXNET to assess how well four metrics derived from remotely sensed vegetation indices (hereafter referred to as proxies) and six remote sensing-based models capture spatial and temporal variations in annual GPP. Specifically, we used the FLUXNET La Thuile data set, which includes several times more sites (144) and site years (422) than previous studies have used. Our results show that remotely sensed proxies and modeled GPP are able to capture significant spatial variation in mean annual GPP in every biome except croplands, but that the percentage of explained variance differed substantially across biomes (10–80%). The ability of remotely sensed proxies and models to explain interannual variability in GPP was even more limited. Remotely sensed proxies explained 40–60% of interannual variance in annual GPP in moisture-limited biomes, including grasslands and shrublands. However, none of the models or remotely sensed proxies explained statistically significant amounts of interannual variation in GPP in croplands, evergreen needleleaf forests, or deciduous broadleaf forests. Robust and repeatable characterization of spatiotemporal variability in carbon budgets is critically important and the carbon cycle science community is increasingly relying on remotely sensing data. Our analyses highlight the power of remote sensing-based models, but also provide bounds on the uncertainties associated with these models. Uncertainty in flux tower GPP, and difference between the footprints of MODIS pixels and flux tower measurements are acknowledged as unresolved challenges.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Copernicus Publications on behalf of the European Geosciences Union. The published article can be found at: http://www.biogeosciences.net/