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

Faster turnover of new soil carbon inputs under increased atmospheric CO2

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Rising levels of atmospheric CO2 frequently stimulate plant inputs to soil, but the consequences of these changes for soil carbon (C) dynamics are poorly understood. Plant-derived inputs can accumulate in the soil and become part of the soil C pool ("new soil C"), or accelerate losses of pre-existing ("old") soil C. The dynamics of the new and old pools will likely differ and alter the long-term fate of soil C, but these separate pools, which can be distinguished through isotopic labeling, have not been considered in past syntheses. Using meta-analysis, we found that while elevated CO2 (ranging from 550 to 800 parts per million by volume) stimulates the accumulation of new soil C in the short term (<1 year), these effects do not persist in the longer term (1-4 years). Elevated CO2 does not affect the decomposition or the size of the old soil C pool over either temporal scale. Our results are inconsistent with predictions of conventional soil C models and suggest that elevated CO2 might increase turnover rates of new soil C. Because increased turnover rates of new soil C limit the potential for additional soil C sequestration, the capacity of land ecosystems to slow the rise in atmospheric CO2 concentrations may be smaller than previously assumed.This work was supported by the U.S. Department of Energy (DOE), Office of Science, Biological and Environmental Research Program, under Award Number DE-SC-0010632. R.P.P. was supported by the U.S. Department of Agriculture NRI CSREES Program and by DOEs Terrestrial Ecosystem Science Program in the Climate and Environmental Sciences Division

Seismic imaging of Santorini: subsurface constraints on caldera collapse and present-day magma recharge

Volcanic calderas are surface depressions formed by roof collapse following evacuation of magma from an underlying reservoir. The mechanisms of caldera formation are debated and predict differences in the evolution of the caldera floor and distinct styles of magma recharge. Here we use a dense, active source, seismic tomography study to reveal the sub-surface physical properties of the Santorini caldera in order to understand caldera formation. We find a ∼3-km-wide, cylindrical low-velocity anomaly in the upper 3 km beneath the north-central portion of the caldera, that lies directly above the pressure source of the 2011-2012 inflation. We interpret this anomaly as a low-density volume caused by excess porosities of between 4% and 28%, with pore spaces filled with hot seawater. Vents that were formed during the first three phases of the 3.6 ka Late Bronze Age (LBA) eruption are located close to the edge of the imaged structure. The correlation between older volcanic vents and the low-velocity anomaly suggests that this feature may be long-lived. We infer that collapse of a limited area of the caldera floor resulted in a high-porosity, low-density cylindrical volume, which formed by either chaotic collapse along reverse faults, wholesale subsidence and infilling with tuffs and ignimbrites, phreatomagmatic fracturing, or a combination of these processes. Phase 4 eruptive vents are located along the margins of the topographic caldera and the velocity structure indicates that coherent down-drop of the wider topographic caldera followed the more limited collapse in the northern caldera. This progressive collapse sequence is consistent with models for multi-stage formation of nested calderas along conjugate reverse and normal faults. The upper crustal density differences inferred from the seismic velocity model predict differences in subsurface gravitational loading that correlate with the location of 2011-2012 edifice inflation. This result supports the hypothesis that sub-surface density anomalies may influence present-day magma recharge events. We postulate that past collapses and the resulting topographical and density variations at Santorini influence magma focusing between eruptive cycles, a feedback process that may be important in other volcanoes

Left gaze bias in humans, rhesus monkeys and domestic dogs

While viewing faces, human adults often demonstrate a natural gaze bias towards the left visual field, that is, the right side of the viewee’s face is often inspected first and for longer periods. Using a preferential looking paradigm, we demonstrate that this bias is neither uniquely human nor limited to primates, and provide evidence to help elucidate its biological function within a broader social cognitive framework. We observed that 6-month-old infants showed a wider tendency for left gaze preference towards objects and faces of different species and orientation, while in adults the bias appears only towards upright human faces. Rhesus monkeys showed a left gaze bias towards upright human and monkey faces, but not towards inverted faces. Domestic dogs, however, only demonstrated a left gaze bias towards human faces, but not towards monkey or dog faces, nor to inanimate object images. Our findings suggest that face- and species-sensitive gaze asymmetry is more widespread in the animal kingdom than previously recognised, is not constrained by attentional or scanning bias, and could be shaped by experience to develop adaptive behavioural significance

Rehabilitation of memory following brain injury (ReMemBrIn): study protocol for a randomised controlled trial

Background Impairments of memory are commonly reported by people with traumatic brain injuries (TBI). Such deficits are persistent, debilitating, and can severely impact quality of life. Currently, many do not routinely receive follow-up appointments for residual memory problems following discharge. Methods/Design This is a multi-centre, randomised controlled trial investigating the clinical and cost-effectiveness of a group-based memory rehabilitation programme. Three hundred and twelve people with a traumatic brain injury will be randomised from four centres. Participants will be eligible if they had a traumatic brain injury more than 3 months prior to recruitment, have memory problems, are 18 to 69 years of age, are able to travel to one of our centres and attend group sessions, and are able to give informed consent. Participants will be randomised in clusters of 4 to 6 to the group rehabilitation intervention or to usual care. Intervention groups will receive 10 weekly sessions of a manualised memory rehabilitation programme, which has been developed in previous pilot studies. The intervention will include restitution strategies to retrain impaired memory functions and compensation strategies to enable participants to cope with their memory problems. All participants will receive a follow-up postal questionnaire and an assessment by a research assistant at 6 and 12 months post-randomisation. The primary outcome is the Everyday Memory Questionnaire at 6 months. Secondary outcomes include the Rivermead Behavioural Memory Test-3, General Health Questionnaire-30, health related quality of life, cost-effectiveness analysis determined by the EQ-5D and a service use questionnaire, individual goal attainment, European Brain Injury Questionnaire (patient and relative versions), and the Everyday Memory Questionnaire-relative version. The primary analysis will be based on intention to treat. A mixed-model regression analysis of the Everyday Memory Questionnaire at 6 months will be used to estimate the effect of the group memory rehabilitation programme. Discussion The study will hopefully provide robust evidence regarding the clinical and cost-effectiveness of a group-based memory rehabilitation intervention for civilians and military personnel following TBI. We discuss our decision-making regarding choice of outcome measures and control group, and the unique challenges to recruiting people with memory problems to trials

Bovine colostrum supplementation and upper respiratory symptoms during exercise training: a systematic review and meta-analysis of randomised controlled trials

Abstract Background Bovine colostrum is proposed as a nutritional countermeasure to the risk of upper respiratory symptoms (URS) during exercise training. The aim of this systematic review and meta-analysis was to estimate the size of the effect of bovine colostrum supplementation on URS. Methods Databases (CDSR, CENTRAL, Cinahl, ClinicalTrials.gov, Current Controlled Trials, DARE, EMBASE, Medline, PROSPERO and Web of Science) of published, unpublished and ongoing studies were searched for randomised controlled trials of healthy adults (≥18 years), evaluating the effect of oral bovine colostrum supplementation compared to a concurrent control group on URS. Results Five trials (152 participants) met the inclusion criteria, all of which involved individuals involved in regular exercise training. Over an 8–12 week follow-up period, bovine colostrum supplementation when compared to placebo significantly reduced the incidence rate of URS days (rate ratio 0.56, 95 % confidence intervals 0.43 to 0.72, P value < 0.001) and URS episodes (0.62, 0.40 to 0.99, P value = 0.04) by 44 and 38 % respectively. There were limited data and considerable variation in results of included studies for duration of URS episodes hence a meta-analysis of this outcome was deemed inappropriate. The risk of bias assessment in this review was hindered by poor reporting practices of included studies. Due to incomplete reporting of study methods, four of the five studies were judged to have a moderate or high risk of overall bias. Our findings must be interpreted in relation to quantity and quality of the available evidence. Conclusions The present systematic review and meta-analysis provides evidence that bovine colostrum supplementation may be effective in preventing the incidence of URS days and episodes in adults engaged in exercise training. The fact that the majority of included studies did not report significant effects on URS outcomes mitigates concerns about publication bias. The point estimates of the random-effects meta-analyses are greater than the smallest clinically important difference, but the low precision of the individual study estimates means the evidence presented in this review needs to be followed up with an appropriately designed and adequately powered, randomised control trial

Clinical features and predictors of mortality in admitted patients with community- and hospital-acquired legionellosis: A Danish historical cohort study

<p>Abstract</p> <p>Background</p> <p>Legionella is a common cause of bacterial pneumonia. Community-acquired [CAL] and hospital-acquired legionellosis [HAL] may have different presentations and outcome. We aimed to compare clinical characteristics and examine predictors of mortality for CAL and HAL.</p> <p>Methods</p> <p>We identified hospitalized cases of legionellosis in 4 Danish counties from January 1995 to December 2005 using the Danish national surveillance system and databases at departments of clinical microbiology. Clinical and laboratory data were retrieved from medical records; vital status was obtained from the Danish Civil Registration System. We calculated 30- and 90-day case fatality rates and identified independent predictors of mortality using logistic regression analyses.</p> <p>Results</p> <p>We included 272 cases of CAL and 60 cases of HAL. Signs and symptoms of HAL were less pronounced than for CAL and time from in-hospital symptoms to legionellosis diagnosis was shorter for CAL than for HAL (5.5 days vs. 12 days p < 0.001). Thirty-day case fatality was 12.9% for CAL and 33.3% for HAL; similarly 90-day case fatalities in the two groups were 15.8% and 55.0%, respectively. In a logistic regression analysis (excluding symptoms and laboratory tests) age >65 years (OR = 2.6, 95% CI: 1.1-5.9) and Charlson comorbidty index ≥2 (OR = 2.7, 95% CI: 1.1-6.5) were associated with an increased risk of death in CAL. We identified no statistically significant predictors of 30-day mortality in HAL.</p> <p>Conclusions</p> <p>Signs and symptoms were less pronounced in HAL compared to CAL. Conversely, 30-day case fatality was almost 3 times higher. Clinical awareness is important for the timely diagnosis and treatment especially of HAL. There is a need for further studies of prognostic factors in order to improve the therapeutic approach to legionellosis and potentially reduce mortality.</p

Behaviour and Physiology: The Thermal Strategy of Leatherback Turtles

Background: Adult leatherback turtles (Dermochelys coriacea) exhibit thermal gradients between their bodies and the environment of $8uC in sub-polar waters and #4uC in the tropics. There has been no direct evidence for thermoregulation in leatherbacks although modelling and morphological studies have given an indication of how thermoregulation may be achieved. Methodology/Principal Findings: We show for the first time that leatherbacks are indeed capable of thermoregulation from studies on juvenile leatherbacks of 16 and 37 kg. In cold water (, 25uC), flipper stroke frequency increased, heat loss through the plastron, carapace and flippers was minimized, and a positive thermal gradient of up to 2.3uC was maintained between body and environment. In warm water (25 – 31uC), turtles were inactive and heat loss through their plastron, carapace and flippers increased. The thermal gradient was minimized (0.5uC). Using a scaling model, we estimate that a 300 kg adult leatherback is able to maintain a maximum thermal gradient of 18.2uC in cold sub-polar waters. Conclusions/Significance: In juvenile leatherbacks, heat gain is controlled behaviourally by increasing activity while heat flux is regulated physiologically, presumably by regulation of blood flow distribution. Hence, harnessing physiology and behaviour allows leatherbacks to keep warm while foraging in cold sub-polar waters and to prevent overheating in

Genetics of decayed sexual traits in a parasitoid wasp with endosymbiont-induced asexuality.

Trait decay may occur when selective pressures shift, owing to changes in environment or life style, rendering formerly adaptive traits non-functional or even maladaptive. It remains largely unknown if such decay would stem from multiple mutations with small effects or rather involve few loci with major phenotypic effects. Here, we investigate the decay of female sexual traits, and the genetic causes thereof, in a transition from haplodiploid sexual reproduction to endosymbiont-induced asexual reproduction in the parasitoid wasp Asobara japonica. We take advantage of the fact that asexual females cured of their endosymbionts produce sons instead of daughters, and that these sons can be crossed with sexual females. By combining behavioral experiments with crosses designed to introgress alleles from the asexual into the sexual genome, we found that sexual attractiveness, mating, egg fertilization and plastic adjustment of offspring sex ratio (in response to variation in local mate competition) are decayed in asexual A. japonica females. Furthermore, introgression experiments revealed that the propensity for cured asexual females to produce only sons (because of decayed sexual attractiveness, mating behavior and/or egg fertilization) is likely caused by recessive genetic effects at a single locus. Recessive effects were also found to cause decay of plastic sex-ratio adjustment under variable levels of local mate competition. Our results suggest that few recessive mutations drive decay of female sexual traits, at least in asexual species deriving from haplodiploid sexual ancestors