Probabilistic Risk Analysis and Margin Process for a Flexible Thermal Protection System

Atmospheric entry vehicle thermal protection systems are margined due to the uncertainties that exist in entry aeroheating environments and the thermal response of the materials and structures. Entry vehicle thermal protections systems are traditionally over-margined for the heat loads that are experienced along the entry trajectory by designing to survive stacked worst-case scenarios. Additionally, the conventional heat shield design and margin process offers very little insight into the risk of over-temperature during flight and the corresponding reliability of the heat shield performance. A probabilistic margin process can be used to appropriately margin the thermal protection system based on rigorously calculated risk of failure. This probabilistic margin process allows engineers to make informed aeroshell design, entry-trajectory design, and risk trades while preventing excessive margin from being applied. This study presents the methods of the probabilistic margin process and how the uncertainty analysis is used to determine the reliability of the entry vehicle thermal protection system and associated risks of failure

Crosstalk between the M1 muscarinic acetylcholine receptor and the endocannabinoid system: A relevance for Alzheimer's disease?

Alzheimer's disease (AD) is a neurodegenerative disorder which accounts for 60-70% of the 50 million worldwide cases of dementia and is characterised by cognitive impairments, many of which have long been associated with dysfunction of the cholinergic system. Although the M muscarinic acetylcholine receptor (mAChR) is considered a promising drug target for AD, ligands targeting this receptor have so far been unsuccessful in clinical trials. As modulatory receptors to cholinergic transmission, the endocannabinoid system may be a promising drug target to allow fine tuning of the cholinergic system. Furthermore, disease-related changes have been found in the endocannabinoid system during AD progression and indeed targeting the endocannabinoid system at specific disease stages alleviates cognitive symptoms in numerous mouse models of AD. Here we review the role of the endocannabinoid system in AD, and its crosstalk with mAChRs as a potential drug target for cholinergic dysfunction. [Abstract copyright: Copyright © 2019. Published by Elsevier Inc.

Integrating methods for determining length-at-age to improve growth estimates for two large scombrids

Fish growth is commonly estimated from length-at-age data obtained from otoliths. There are several techniques for estimating length-at-age from otoliths including 1) direct observed counts of annual increments; 2) age adjustment based on a categorization of otolith margins; 3) age adjustment based on known periods of spawning and annuli formation; 4) back-calculation to all annuli, and 5) back-calculation to the last annulus only. In this study we compared growth estimates (von Bertalanffy growth functions) obtained from the above five methods for estimating length-at-age from otoliths for two large scombrids: narrow-barred Spanish mackerel (Scomberomorus commerson) and broad-barred king mackerel (Scomberomorus semifasciatus). Likelihood ratio tests revealed that the largest differences in growth occurred between the back-calculation methods and the observed and adjusted methods for both species of mackerel. The pattern, however, was more pronounced for S. commerson than for S. semifasciatus, because of the pronounced effect of gear selectivity demonstrated for S. commerson. We propose a method of substituting length-at-age data from observed or adjusted methods with back-calculated length-at-age data to provide more appropriate estimates of population growth than those obtained with the individual methods alone, particularly when faster growing young fish are disproportionately selected for. Substitution of observed or adjusted length-at-age data with back-calculated length-at-age data provided more realistic estimates of length for younger ages than observed or adjusted methods as well as more realistic estimates of mean maximum length than those derived from backcalculation methods alone

The use of chemogenetic approaches to study the physiological roles of muscarinic acetylcholine receptors in the central nervous system

Chemical genetic has played an important role in linking specific G protein-coupled receptor (GPCR) signalling to cellular processes involved in central nervous system (CNS) functions. Key to this approach has been the modification of receptor properties such that receptors no longer respond to endogenous ligands but rather can be activated selectively by synthetic ligands. Such modified receptors have been called Receptors Activated Solely by Synthetic Ligands (RASSLs) or Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Unlike knock-out animal models which allow detection of phenotypic changes caused by loss of receptor functions, RASSL and DREADD receptors offer the possibility of rescuing "knock-out" phenotypic deficits by administration of the synthetic ligands. Here we describe the use of these modified receptors in defining the physiological role of GPCRs and validation of receptors as drug targets

An evolutionary perspective on the kinome of malaria parasites

Malaria parasites belong to an ancient lineage that diverged very early from the main branch of eukaryotes. The approximately 90-member plasmodial kinome includes a majority of eukaryotic protein kinases that clearly cluster within the AGC, CMGC, TKL, CaMK and CK1 groups found in yeast, plants and mammals, testifying to the ancient ancestry of these families. However, several hundred millions years of independent evolution, and the specific pressures brought about by first a photosynthetic and then a parasitic lifestyle, led to the emergence of unique features in the plasmodial kinome. These include taxon-restricted kinase families, and unique peculiarities of individual enzymes even when they have homologues in other eukaryotes. Here, we merge essential aspects of all three malaria-related communications that were presented at the Evolution of Protein Phosphorylation meeting, and propose an integrated discussion of the specific features of the parasite's kinome and phosphoproteome

Assessment of novel gear designs to reduce interactions between species

This project tested modified gillnets designed by commercial net fishers in the Queensland East Coast Inshore Finfish Fishery (ECIFF) to try and identify gears that would mitigate and/or improve interactions between fishing nets and Species of Conservation Interest (SOCI). The study also documents previously unrecognised initiatives by pro-active commercial net fishers that reflect a conservation-minded approach to their fishing practices, which is the opposite of what is perceived publicly. Between 2011 and 2014, scientists from James Cook University and the Queensland Department of Agriculture and Fisheries teamed with commercial fishers representing the Queensland Seafood Industry Association and the Moreton Bay Seafood Industry Association to conduct field trials of various modified net designs under normal fishery conditions. Trials were conducted in Moreton Bay (southern part of the fishery) and Bowling Green Bay (northern) and tested different net designs developed by fishers to improve the nature of interactions between net fishing gear and SOCI

Distinct phosphorylation clusters determines the signalling outcome of the free fatty acid receptor FFA4/GPR120

It is established that long-chain free fatty acids including ω-3 fatty acids mediate an array of biological responses through members of the free fatty acid receptor family, which includes FFA4. However, the signalling mechanisms and modes of regulation of this receptor class remain unclear. Here we employ mass spectrometry to determine that phosphorylation of mouse (m)FFAR4 occurs at five serine and threonine residues clustered in two separable regions of the C terminal tail, designated cluster 1 (Thr347, Thr349 and Ser350) and cluster 2 (Ser357 and Ser361). Mutation of these phospho-acceptor sites to alanine completely prevented phosphorylation of mFFA4 but did not limit receptor coupling to ERK1/2 activation. Rather an inhibitor of Gq/11 proteins completely prevented receptor signalling to ERK1/2. In contrast, the recruitment of arrestin 3, receptor internalization and activation of Akt were regulated by mFFA4 phosphorylation. The analysis of mFFA4 phosphorylation-dependent signalling was extended further by selective mutations of the phospho-acceptor sites. Mutations within cluster 2 did not affect agonist activation of Akt but instead significantly compromised receptor internalization and arrestin 3 recruitment. Distinctly, mutation of the phospho-acceptor sites within cluster 1 had no effect on receptor internalization and a less extensive effect on arrestin 3 recruitment, but significantly uncoupled the receptor from Akt activation. These unique observations define differential effects on signalling mediated by phosphorylation at distinct locations. This hallmark feature supports the possibility that the signalling outcome of mFFA4 activation can be determined by the pattern of phosphorylation (phosphorylation barcode) at the C-terminus of the receptor

Movements and space use of giant trevally in coral reef habitats and the importance of environmental drivers

Background: Effective conservation of large predators requires a broad understanding of their ecology. Caranx ignobilis is a large marine predator well represented in coral reef environments, yet they are poorly studied. Passive acoustic monitoring was used to track the movements of 20 C. ignobilis at offshore reefs in the central Great Barrier Reef from 2012 to 2014. Using a modelling approach, temporal changes in movement patterns of C. ignobilis were explored to determine if individuals exhibited predictable movement patterns. The effects of biological and environmental variables on monthly space use, daily presence and hourly depth use were investigated to define any response to environmental changes. Results: Caranx ignobilis typically remained at their capture reef with 98.8% of detections recorded at these locations. Individuals were recorded in the study site for periods from 9 to 335 days (mean = 125.9) with a mean residency index of 0.53, indicating movements away from the reef or out of detection range occurred on the scale of days. Inter-reef movements from only three individuals were recorded which coincided with the summer full moon so may have been related to spawning behaviour. Environmental drivers were correlated with daily presence and hourly depth use of C. ignobilis but had little influence on monthly space use. There was little or no effect of fish size on space use, presence and depth use. Conclusion: By improving the current understanding of movement patterns of this large teleost among individual coral reefs, the results of this study reveal that site attachment may be present and that environmental parameters play a role in observed movement patterns related to depth and presence. These data provide useful information for the development of management plans, particularly in relation to space-based protection

Editorial for Advances in G Protein-Coupled Receptor Signal Transduction Special Issue

No abstract available

N-methyl-D-aspartate receptors mediate the phosphorylation and desensitization of muscarinic receptors in cerebellar granule neurons.

Changes in synaptic strength mediated by ionotropic glutamate N-methyl-D-asparate (NMDA) receptors is generally considered to be the molecular mechanism underlying memory and learning. NMDA receptors themselves are subject to regulation through signaling pathways that are activated by G-protein-coupled receptors (GPCRs). In this study we investigate the ability of NMDA receptors to regulate the signaling of GPCRs by focusing on the G(q/11)-coupled M(3)-muscarinic receptor expressed endogenously in mouse cerebellar granule neurons. We show that NMDA receptor activation results in the phosphorylation and desensitization of M(3)-muscarinic receptors through a mechanism dependent on NMDA-mediated calcium influx and the activity of calcium-calmodulin-dependent protein kinase II. Our study reveals a complex pattern of regulation where GPCRs (M(3)-muscarinic) and NMDA receptors can feedback on each other in a process that is likely to influence the threshold value of signaling networks involved in synaptic plasticity