The phospholipase A2 pathway controls a synaptic cholesterol ester cycle and synapse damage

The cellular prion protein (PrPC) acts as a scaffold protein that organises signalling complexes. In synaptosomes, the aggregation of PrPC by amyloid-β (Aβ) oligomers attracts and activates cytoplasmic phospholipase A2 (cPLA2), leading to synapse degeneration. The signalling platform is dependent on cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs). The activation of cPLA2 requires cholesterol released from cholesterol esters by cholesterol ester hydrolases (CEHs), enzymes dependent upon platelet activating factor (PAF) released by activated cPLA2 This demonstrates a positive feedback system in which activated cPLA2 increased cholesterol concentrations, which in turn facilitated cPLA2 activation. PAF was also required for the incorporation of the tyrosine kinase Fyn and cyclooxygenase (COX)-2 into Aβ-PrPC-cPLA2 complexes. As a failure to deactivate signalling complexes can lead to pathology, the mechanisms involved in their dispersal were studied. PAF facilitated the incorporation of acyl-coenzyme A:cholesterol acyltransferase (ACAT)-1 into Aβ-PrPC-cPLA2-COX-2-Fyn complexes. The esterification of cholesterol reduced cholesterol concentrations, causing dispersal of Aβ-PrPC-cPLA2-COX-2-Fyn complexes and the cessation of signalling. This study identifies PAF as a key mediator regulating the cholesterol ester cycle, activation of cPLA2 and COX-2 within synapses, and synapse damage

State Dependence of Stimulus-Induced Variability Tuning in Macaque MT

Behavioral states marked by varying levels of arousal and attention modulate some properties of cortical responses (e.g. average firing rates or pairwise correlations), yet it is not fully understood what drives these response changes and how they might affect downstream stimulus decoding. Here we show that changes in state modulate the tuning of response variance-to-mean ratios (Fano factors) in a fashion that is neither predicted by a Poisson spiking model nor changes in the mean firing rate, with a substantial effect on stimulus discriminability. We recorded motion-sensitive neurons in middle temporal cortex (MT) in two states: alert fixation and light, opioid anesthesia. Anesthesia tended to lower average spike counts, without decreasing trial-to-trial variability compared to the alert state. Under anesthesia, within-trial fluctuations in excitability were correlated over longer time scales compared to the alert state, creating supra-Poisson Fano factors. In contrast, alert-state MT neurons have higher mean firing rates and largely sub-Poisson variability that is stimulus-dependent and cannot be explained by firing rate differences alone. The absence of such stimulus-induced variability tuning in the anesthetized state suggests different sources of variability between states. A simple model explains state-dependent shifts in the distribution of observed Fano factors via a suppression in the variance of gain fluctuations in the alert state. A population model with stimulus-induced variability tuning and behaviorally constrained information-limiting correlations explores the potential enhancement in stimulus discriminability by the cortical population in the alert state.Comment: 36 pages, 18 figure

Space tug propulsion system failure mode, effects and criticality analysis

For purposes of the study, the propulsion system was considered as consisting of the following: (1) main engine system, (2) auxiliary propulsion system, (3) pneumatic system, (4) hydrogen feed, fill, drain and vent system, (5) oxygen feed, fill, drain and vent system, and (6) helium reentry purge system. Each component was critically examined to identify possible failure modes and the subsequent effect on mission success. Each space tug mission consists of three phases: launch to separation from shuttle, separation to redocking, and redocking to landing. The analysis considered the results of failure of a component during each phase of the mission. After the failure modes of each component were tabulated, those components whose failure would result in possible or certain loss of mission or inability to return the Tug to ground were identified as critical components and a criticality number determined for each. The criticality number of a component denotes the number of mission failures in one million missions due to the loss of that component. A total of 68 components were identified as critical with criticality numbers ranging from 1 to 2990

Causal structure of the entanglement renormalization ansatz

We show that the multiscale entanglement renormalization ansatz (MERA) can be reformulated in terms of a causality constraint on discrete quantum dynamics. This causal structure is that of de Sitter space with a flat spacelike boundary, where the volume of a spacetime region corresponds to the number of variational parameters it contains. This result clarifies the nature of the ansatz, and suggests a generalization to quantum field theory. It also constitutes an independent justification of the connection between MERA and hyperbolic geometry which was proposed as a concrete implementation of the AdS-CFT correspondence

Freak Waves in Random Oceanic Sea States

Freak waves are very large, rare events in a random ocean wave train. Here we study the numerical generation of freak waves in a random sea state characterized by the JONSWAP power spectrum. We assume, to cubic order in nonlinearity, that the wave dynamics are governed by the nonlinear Schroedinger (NLS) equation. We identify two parameters in the power spectrum that control the nonlinear dynamics: the Phillips parameter $\alpha$ and the enhancement coefficient $\gamma$. We discuss how freak waves in a random sea state are more likely to occur for large values of $\alpha$ and $\gamma$. Our results are supported by extensive numerical simulations of the NLS equation with random initial conditions. Comparison with linear simulations are also reported.Comment: 7 pages, 6 figures, to be published in Phys. Rev. Let

Enzymes as Feed Additive to Aid in Responses Against Eimeria Species in Coccidia-Vaccinated Broilers Fed Corn-Soybean Meal Diets with Different Protein Levels

This research aimed to evaluate the effects of adding a combination of exogenous enzymes to starter diets varying in protein content and fed to broilers vaccinated at day of hatch with live oocysts and then challenged with mixed Eimeria spp. Five hundred four 1-d-old male Cobb-500 chickens were distributed in 72 cages. The design consisted of 12 treatments. Three anticoccidial control programs [ionophore (IO), coccidian vaccine (COV), and coccidia-vaccine + enzymes (COV + EC)] were evaluated under 3 CP levels (19, 21, and 23%), and 3 unmedicated-uninfected (UU) negative controls were included for each one of the protein levels. All chickens except those in unmedicated-uninfected negative controls were infected at 17 d of age with a mixed oral inoculum of Eimeria acervulina, Eimeria maxima, and Eimeria tenella. Live performance, lesion scores, oocyst counts, and samples for gut microflora profiles were evaluated 7 d postinfection. Ileal digestibility of amino acids (IDAA) was determined 8 d postinfection. Microbial communities (MC) were analyzed by G + C%, microbial numbers were counted by flow cytometry, and IgA concentrations were measured by ELISA. The lowest CP diets had poorer (P ≤ 0.001) BW gain and feed conversion ratio in the preinfection period. Coccidia-vaccinated broilers had lower performance than the ones fed ionophore diets during pre- and postchallenge periods. Intestinal lesion scores were affected (P ≤ 0.05) by anticoccidial control programs, but responses changed according to gut section. Feed additives or vaccination had no effect (P ≥ 0.05) on IDAA, and diets with 23% CP had the lowest (P ≤ 0.001) IDAA. Coccidial infection had no effect on MC numbers in the ileum but reduced MC numbers in ceca and suppressed ileal IgA production. The COV + EC treatment modulated MC during mixed coccidiosis infection but did not significantly improve chicken performance. Results indicated that feed enzymes may be used to modulate the gut microflora of cocci-vaccinated broiler chickens

Early multi-wavelength emission from Gamma-ray Bursts: from Gamma-ray to X-ray

The study of the early high-energy emission from both long and short Gamma-ray bursts has been revolutionized by the Swift mission. The rapid response of Swift shows that the non-thermal X-ray emission transitions smoothly from the prompt phase into a decaying phase whatever the details of the light curve. The decay is often categorized by a steep-to-shallow transition suggesting that the prompt emission and the afterglow are two distinct emission components. In those GRBs with an initially steeply-decaying X-ray light curve we are probably seeing off-axis emission due to termination of intense central engine activity. This phase is usually followed, within the first hour, by a shallow decay, giving the appearance of a late emission hump. The late emission hump can last for up to a day, and hence, although faint, is energetically very significant. The energy emitted during the late emission hump is very likely due to the forward shock being constantly refreshed by either late central engine activity or less relativistic material emitted during the prompt phase. In other GRBs the early X-ray emission decays gradually following the prompt emission with no evidence for early temporal breaks, and in these bursts the emission may be dominated by classical afterglow emission from the external shock as the relativistic jet is slowed by interaction with the surrounding circum-burst medium. At least half of the GRBs observed by Swift also show erratic X-ray flaring behaviour, usually within the first few hours. The properties of the X-ray flares suggest that they are due to central engine activity. Overall, the observed wide variety of early high-energy phenomena pose a major challenge to GRB models.Comment: Accepted for publication in the New Journal of Physics focus issue on Gamma Ray Burst

Pre-registration as behaviour: developing an evidence-based intervention specification to increase pre-registration uptake by researchers using the Behaviour Change Wheel

Data availability statement: The data described in this article are openly available in the Open Science Framework at https://osf.io/dfcem/.Open Scholarship: This article has earned the Center for Open Science badges for Open Data, Open Materials and Preregistered. The data and materials are openly accessible at https://osf.io/dfcem/, https://doi.org/10.17605/osf.io/dfcem and https://osf.io/9pvn6.Copyright © 2022 The Author(s). Pre-registration is an open research practice that can mitigate against questionable research practices and contribute to enhanced research outcomes, such as increased research transparency. This paper explores barriers and enablers to pre-registration, and develops an evidence-based behaviour change intervention specification to increase its uptake. The Behaviour Change Wheel (BCW) framework of intervention development and COM-B model of behaviour change were used to inform the development of a mixed-methods online questionnaire, assessing barriers and enablers to pre-registration. Data were collected from 18-05-2020 to 12-07-2020, and explored using descriptive statistics, reflexive thematic analysis, and COM-B. BCW was used to develop an intervention specification. Respondents were researchers (n = 105) who were mostly engaged in psychological research (71%) and had pre-registered before (75%). Insufficient knowledge and skill (psychological capability), social support (social opportunity), time (physical opportunity), and incentivisation (reflective motivation) were the most substantial barriers to pre-registration, whereas belief in pre-registration contributing to desirable research outcomes (reflective motivation) was the most substantial enabler. These findings informed the development of an intervention specification to increase pre-registration uptake by researchers. This paper demonstrates the strong potential of BCW to facilitate open research practices. The identified barriers and enablers, intervention specification, and the behaviour change approach outlined, may be used to increase pre-registration uptake; for example, developing new or refining existing training and incentivisation interventions. This paper may inspire others to consider the strong potential of BCW to facilitate open research practices and so contribute to enhanced research outcomes