Human Mas-related G protein-coupled receptors-X1 induce chemokine receptor 2 expression in rat dorsal root ganglia neurons and release of chemokine ligand 2 from the human LAD-2 mast cell line

Primate-specific Mas-related G protein-coupled receptors-X1 (MRGPR-X1) are highly enriched in dorsal root ganglia (DRG) neurons and induce acute pain. Herein, we analyzed effects of MRGPR-X1 on serum response factors (SRF) or nuclear factors of activated T cells (NFAT), which control expression of various markers of chronic pain. Using HEK293, DRG neuron-derived F11 cells and cultured rat DRG neurons recombinantly expressing human MRGPR-X1, we found activation of a SRF reporter gene construct and induction of the early growth response protein-1 via extracellular signal-regulated kinases-1/2 known to play a significant role in the development of inflammatory pain. Furthermore, we observed MRGPR-X1-induced up-regulation of the chemokine receptor 2 (CCR2) via NFAT, which is considered as a key event in the onset of neuropathic pain and, so far, has not yet been described for any endogenous neuropeptide. Up-regulation of CCR2 is often associated with increased release of its endogenous agonist chemokine ligand 2 (CCL2). We also found MRGPR-X1-promoted release of CCL2 in a human connective tissue mast cell line endogenously expressing MRGPR-X1. Thus, we provide first evidence to suggest that MRGPR-X1 induce expression of chronic pain markers in DRG neurons and propose a so far unidentified signaling circuit that enhances chemokine signaling by acting on two distinct yet functionally co-operating cell types. Given the important role of chemokine signaling in pain chronification, we propose that interruption of this signaling circuit might be a promising new strategy to alleviate chemokine-promoted pain

Unraveling the function of Arabidopsis thaliana OS9 in the endoplasmic reticulum-associated degradation of glycoproteins

In the endoplasmic reticulum, immature polypeptides coincide with terminally misfolded proteins. Consequently, cells need a well-balanced quality control system, which decides about the fate of individual proteins and maintains protein homeostasis. Misfolded and unassembled proteins are sent for destruction via the endoplasmic reticulum-associated degradation (ERAD) machinery to prevent the accumulation of potentially toxic protein aggregates. Here, we report the identification of Arabidopsis thaliana OS9 as a component of the plant ERAD pathway. OS9 is an ER-resident glycoprotein containing a mannose-6-phosphate receptor homology domain, which is also found in yeast and mammalian lectins involved in ERAD. OS9 fused to the C-terminal domain of YOS9 can complement the ERAD defect of the corresponding yeast Δyos9 mutant. An A. thaliana OS9 loss-of-function line suppresses the severe growth phenotype of the bri1-5 and bri1-9 mutant plants, which harbour mutated forms of the brassinosteroid receptor BRI1. Co-immunoprecipitation studies demonstrated that OS9 associates with Arabidopsis SEL1L/HRD3, which is part of the plant ERAD complex and with the ERAD substrates BRI1-5 and BRI1-9, but only the binding to BRI1-5 occurs in a glycan-dependent way. OS9-deficiency results in activation of the unfolded protein response and reduces salt tolerance, highlighting the role of OS9 during ER stress. We propose that OS9 is a component of the plant ERAD machinery and may act specifically in the glycoprotein degradation pathway

Validity and usefulness of members reports of implementation progress in a quality improvement initiative: findings from the Team Check-up Tool (TCT)

<p>Abstract</p> <p>Background</p> <p>Team-based interventions are effective for improving safety and quality of healthcare. However, contextual factors, such as team functioning, leadership, and organizational support, can vary significantly across teams and affect the level of implementation success. Yet, the science for measuring context is immature. The goal of this study is to validate measures from a short instrument tailored to track dynamic context and progress for a team-based quality improvement (QI) intervention.</p> <p>Methods</p> <p>Design: Secondary cross-sectional and longitudinal analysis of data from a clustered randomized controlled trial (RCT) of a team-based quality improvement intervention to reduce central line-associated bloodstream infection (CLABSI) rates in intensive care units (ICUs).</p> <p>Setting: Forty-six ICUs located within 35 faith-based, not-for-profit community hospitals across 12 states in the U.S.</p> <p>Population: Team members participating in an ICU-based QI intervention.</p> <p>Measures: The primary measure is the Team Check-up Tool (TCT), an original instrument that assesses context and progress of a team-based QI intervention. The TCT is administered monthly. Validation measures include CLABSI rate, Team Functioning Survey (TFS) and Practice Environment Scale (PES) from the Nursing Work Index.</p> <p>Analysis: Temporal stability, responsiveness and validity of the TCT.</p> <p>Results</p> <p>We found evidence supporting the temporal stability, construct validity, and responsiveness of TCT measures of intervention activities, perceived group-level behaviors, and barriers to team progress.</p> <p>Conclusions</p> <p>The TCT demonstrates good measurement reliability, validity, and responsiveness. By having more validated measures on implementation context, researchers can more readily conduct rigorous studies to identify contextual variables linked to key intervention and patient outcomes and strengthen the evidence base on successful spread of efficacious team-based interventions. QI teams participating in an intervention should also find data from a validated tool useful for identifying opportunities to improve their own implementation.</p

Bonobos, chimpanzees, gorillas, and orang utans use feature and spatial cues in two spatial memory tasks

Animals commonly use feature and spatial strategies when remembering places of interest such as food sources or hiding places. We conducted three experiments with great apes to investigate strategy preferences and factors that may shape them. In the first experiment, we trained 17 apes to remember 12 different food locations on the floor of their sleeping room. The 12 food locations were associated with one feature cue, so that feature and spatial cues were confounded. In a single test session, we brought the cues into conflict and found that apes, irrespective of species, showed a preference for a feature strategy. In the second experiment, we used a similar procedure and trained 25 apes to remember one food location on a platform in front of them. On average, apes preferred to use a feature strategy but some individuals relied on a spatial strategy. In the final experiment, we investigated whether training might influence strategy preferences. We tested 21 apes in the platform set-up and found that apes used both, feature and spatial strategies irrespective of training. We conclude that apes can use feature and spatial strategies to remember the location of hidden food items, but that task demands (e.g. different numbers of search locations) can influence strategy preferences. We found no evidence, however, for the role of training in shaping these preferences

Bcl-2-regulated cell death signalling in the prevention of autoimmunity

Cell death mediated through the intrinsic, Bcl-2-regulated mitochondrial apoptosis signalling pathway is critical for lymphocyte development and the establishment of central and maintenance of peripheral tolerance. Defects in Bcl-2-regulated cell death signalling have been reported to cause or correlate with autoimmunity in mice and men. This review focuses on the role of Bcl-2 family proteins implicated in the development of autoimmune disorders and their potential as targets for therapeutic intervention

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Understanding single-station ground motion variability and uncertainty (sigma) – Lessons learnt from EUROSEISTEST

Accelerometric data from the well-studied valley EUROSEISTEST are used to investigate ground motion uncertainty and variability. We define a simple local ground motion prediction equation (GMPE) and investigate changes in standard deviation (σ) and its components, the between-event variability (τ) and within-event variability (φ). Improving seismological metadata significantly reduces τ (30-50%), which in turn reduces the total σ. Improving site information reduces the systematic site-to-site variability, φS2S (20-30%), in turn reducing φ, and ultimately, σ. Our values of standard deviations are lower than global values from literature, and closer to path-specific than site-specific values. However, our data have insufficient azimuthal coverage for single-path analysis. Certain stations have higher ground-motion variability, possibly due to topography, basin edge or downgoing wave effects. Sensitivity checks show that 3 recordings per event is a sufficient data selection criterion, however, one of the dataset’s advantages is the large number of recordings per station (9-90) that yields good site term estimates. We examine uncertainty components binning our data with magnitude from 0.01 to 2 s; at smaller magnitudes, τ decreases and φSS increases, possibly due to κ and source-site trade-offs Finally, we investigate the alternative approach of computing φSS using existing GMPEs instead of creating an ad hoc local GMPE. This is important where data are insufficient to create one, or when site-specific PSHA is performed. We show that global GMPEs may still capture φSS, provided that: 1. the magnitude scaling errors are accommodated by the event terms; 2. there are no distance scaling errors (use of a regionally applicable model). Site terms (φS2S) computed by different global GMPEs (using different site-proxies) vary significantly, especially for hard-rock sites. This indicates that GMPEs may be poorly constrained where they are sometimes most needed, i.e. for hard rock