Many-body dissipative particle dynamics simulations of micellization of sodium alkyl sulfates.

We present a study of micelle formation in alkyl sulfate surfactants using the simulation method of many-body dissipative particle dynamics (MDPD). We parametrise our model by tuning the intermolecular interactions in order to reproduce experimental values for the chemical potential and density at room temperature. Using this approach, we find that our model shows good agreement with experimental values for the critical micelle concentration (CMC). Furthermore, we show that our model can accurately predict CMC trends, which result from varying properties such as surfactant tail length and the salt concentration. We apply our model to investigate the effect of aggregation number on various micellar properties, such as the shape of individual micelles and the fraction of bound counterions. We show that micelles become aspherical at large aggregation numbers, in line with experimental predictions, and that longer tail surfactants are generally more spherical at all aggregation numbers compared to those which are shorter. We find excellent agreement between our simulations and experimental values for the degree of counterion binding, a factor that is crucial to accurately studying micellar shape, but one that is typically overlooked in the existing literature.

Unravelling Guest Dynamics in Crystalline Molecular Organics Using 2H Solid-State NMR and Molecular Dynamics Simulation.

2H solid-state NMR and atomistic molecular dynamics (MD) simulations are used to understand the disorder of guest solvent molecules in two cocrystal solvates of the pharmaceutical furosemide. Traditional approaches to interpreting the NMR data fail to provide a coherent model of molecular behavior and indeed give misleading kinetic data. In contrast, the direct prediction of the NMR properties from MD simulation trajectories allows the NMR data to be correctly interpreted in terms of combined jump-type and libration-type motions. Time-independent component analysis of the MD trajectories provides additional insights, particularly for motions that are invisible to NMR. This allows a coherent picture of the dynamics of molecules restricted in molecular-sized cavities to be determined.

Computational predictions of interfacial tension, surface tension, and surfactant adsorption isotherms.

All-atom (AA) molecular dynamics (MD) simulations are employed to predict interfacial tensions (IFT) and surface tensions (ST) of both ionic and non-ionic surfactants. The general AMBER force field (GAFF) and variants are examined in terms of their performance in predicting accurate IFT/ST, γ, values for chosen water models, together with the hydration free energy, ΔGhyd, and density, ρ, predictions for organic bulk phases. A strong correlation is observed between the quality of ρ and γ predictions. Based on the results, the GAFF-LIPID force field, which provides improved ρ predictions is selected for simulating surfactant tail groups. Good γ predictions are obtained with GAFF/GAFF-LIPID parameters and the TIP3P water model for IFT simulations at a water-triolein interface, and for GAFF/GAFF-LIPID parameters together with the OPC4 water model for ST simulations at a water-vacuum interface. Using a combined molecular dynamics-molecular thermodynamics theory (MD-MTT) framework, a mole fraction of C12E6 molecule of 1.477 × 10-6 (from the experimental critical micelle concentration, CMC) gives a simulated surface excess concentration, ΓMAX, of 76 C12E6 molecules at a 36 nm2 water-vacuum surface (3.5 × 10-10 mol cm-2), which corresponds to a simulated ST of 35 mN m-1. The results compare favourably with an experimental ΓMAX of C12E6 of 3.7 × 10-10 mol cm-2 (80 surfactants for a 36 nm2 surface) and experimental ST of C12E6 of 32 mN m-1 at the CMC.

Can cognitive training capitalise on near transfer effects? Limited evidence of transfer following online inhibition training in a randomised-controlled trial.

Despite early promise, cognitive training research has failed to deliver consistent real-world benefits and questions have been raised about the experimental rigour of many studies. Several meta-analyses have suggested that there is little to no evidence for transfer of training from computerised tasks to real-world skills. More targeted training approaches that aim to optimise performance on specific tasks have, however, shown more promising effects. In particular, the use of inhibition training for improving shoot/don't-shoot decision-making has returned positive far transfer effects. In the present work, we tested whether an online inhibition training task could generate near and mid-transfer effects in the context of response inhibition tasks. As there has been relatively little testing of retention effects in the literature to date, we also examined whether any benefits would persist over a 1-month interval. In a pre-registered, randomised-controlled trial, participants (n = 73) were allocated to either an inhibition training programme (six training sessions of a visual search task with singleton distractor) or a closely matched active control task (that omitted the distractor element). We assessed near transfer to a Flanker task, and mid-transfer to a computerised shoot/don't-shoot task. There was evidence for a near transfer effect, but no evidence for mid-transfer. There was also no evidence that the magnitude of training improvement was related to transfer task performance. This finding adds to the growing body of literature questioning the effectiveness of cognitive training. Given previous positive findings, however, there may still be value in continuing to explore the extent to which cognitive training can capitalise on near or mid-transfer effects for performance optimisation.

The functional role of visual information and fixation stillness in the quiet eye.

The final fixation to a target in far-aiming tasks, known as the quiet eye, has been consistently identified as an important perceptual-cognitive variable for task execution. Yet, despite a number of proposed mechanisms it remains unclear whether the fixation itself is driving performance effects or is simply an emergent property of underpinning cognitions. Across two pre-registered studies, novice golfers (n = 127) completed a series of golf putts in a virtual reality simulation to examine the function of the quiet eye in the absence of visual information. In experiment 1 participants maintained a quiet eye fixation even when all visual information was occluded. Visual occlusion did significantly disrupt motor skill accuracy, but the effect was relatively small (89cm vs 105cm radial error, std. beta = 0.25). In experiment 2, a 'noisy eye' was induced using covertly moving fixation points, which disrupted skill execution (p = .04, BF = 318.07, std. beta = -0.25) even though visual input was equivalent across conditions. Overall, the results showed that performers persist with a long pre-shot fixation even in the absence of visual information, and that the stillness of this fixation confers a functional benefit that is not merely related to improved information extraction.

The N-end rule pathway regulates ER stress-induced clusterin release to the cytosol where it directs misfolded proteins for degradation.

Previous work suggests that cell stress induces release of the normally secreted chaperone clusterin (CLU) into the cytosol. We analyzed the localization of CLU in healthy and stressed cells, the mechanism of its cytosolic release, and its interactions with cytosolic misfolded proteins. Key results of this study are the following: (1) full-length CLU is released to the cytosol during stress, (2) the CLU N-terminal D1 residue is recognized by the N-end rule pathway and together with the enzyme ATE1 is essential for cytosolic release, (3) CLU can form stable complexes with cytosolic misfolded proteins and direct them to the proteasome and autophagosomes, and (4) cytosolic CLU protects cells from hypoxic stress and the cytosolic overexpression of an aggregation-prone protein. Collectively, the results suggest that enhanced cytosolic release of CLU is a stress response that can inhibit the toxicity of misfolded proteins and facilitate their targeted degradation via both autophagy and the proteasome.

The perceived control model of falling: developing a unified framework to understand and assess maladaptive fear of falling.

BACKGROUND: fear of falling is common in older adults and can have a profound influence on a variety of behaviours that increase fall risk. However, fear of falling can also have potentially positive outcomes for certain individuals. Without progressing our understanding of mechanisms underlying these contrasting outcomes, it is difficult to clinically manage fear of falling. METHODS: this paper first summarises recent findings on the topic of fear of falling, balance and fall risk-including work highlighting the protective effects of fear. Specific focus is placed on describing how fear of falling influences perceptual, cognitive and motor process in ways that might either increase or reduce fall risk. Finally, it reports the development and validation of a new clinical tool that can be used to assess the maladaptive components of fear of falling. RESULTS: we present a new conceptual framework-the Perceived Control Model of Falling-that describes specific mechanisms through which fear of falling can influence fall risk. The key conceptual advance is the identification of perceived control over situations that threaten one's balance as the crucial factor mediating the relationship between fear and increased fall risk. The new 4-item scale that we develop-the Updated Perceived Control over Falling Scale (UP-COF)-is a valid and reliable tool to clinically assess perceived control. CONCLUSION: this new conceptualisation and tool (UP-COF) allows clinicians to identify individuals for whom fear of falling is likely to increase fall risk, and target specific underlying maladaptive processes such as low perceived control.

A many-body dissipative particle dynamics parametrisation scheme to study behaviour at air-water interfaces.

In this article, we present a general parametrisation scheme for many-body dissipative particle dynamics (MDPD). The scheme is based on matching model components to experimental surface tensions and chemical potentials. This allows us to obtain the correct surface and mixing behaviours of complex, multicomponent systems. The methodology is tested by modelling the behaviour of nonionic polyoxyethylene alkyl ether surfactants at an air/water interface. In particular, the influence of the number of ethylene oxide units in the surfactant head group is investigated. We find good agreement with many experimentally obtained parameters, such as minimum surface area per molecule; and a decrease in the surface tension with increasing surfactant surface density. Moreover, we observe an orientational transition, from surfactants lying directly on the water surface at low surface coverage, to surfactants lying parallel or tilted with respect to the surface normal at high surface coverage. The parametrisation scheme is also extended to cover the zwitterionic surfactant lauryldimethylamine oxide (LDAO), where we provide good predictions for the surface tension at maximum surface coverage. Here, if we exceed this coverage, we are able to demonstrate the spontaneous production of micelles from the surface surfactant layer.

Exploring the role of socioeconomic status and psychological characteristics on talent development in an English soccer academy.

Social factors and psychological characteristics can influence participation and development in talent pathways. However, the interaction between these two factors is relatively unknown. The aim of this study was to investigate the implications of socioeconomic status and psychological characteristics in English academy soccer players (n=58; aged 11 to 16 years). To assess socioeconomic status, participants' home postcodes were coded according to each individual's social classification and credit rating, applying the UK General Registrar Classification system and CameoTM geodemographic database, respectively. Participants also completed the six factor Psychological Characteristics for Developing Excellence Questionnaire (PCDEQ). A classification of 'higher-potentials' (n=19) and 'lower-potentials' (n=19) were applied through coach potential rankings. Data were standardised using z-scores to eliminate age bias and data were analysed using independent sample t-tests. Results showed that higher-potentials derived from families with significantly lower social classifications (p=0.014) and reported higher levels for PCDEQ Factor 3 (coping with performance and developmental pressures) (p=0.007) compared to lower-potentials. This study can be used to support the impetus for researchers and practitioners to consider the role of social factors and psychological characteristics when developing sporting talent. For example, facilitating player-centred development within an academy and, where necessary, providing individuals with additional support.

Clusterin Neutralizes the Inflammatory and Cytotoxic Properties of Extracellular Histones in Sepsis.

Rationale: Extracellular histones, released into the surrounding environment during extensive cell death, promote inflammation and cell death, and these deleterious roles have been well documented in sepsis. Clusterin (CLU) is a ubiquitous extracellular protein that chaperones misfolded proteins and promotes their removal. Objectives: We investigated whether CLU could protect against the deleterious properties of histones. Methods: We assessed CLU and histone expression in patients with sepsis and evaluated the protective role of CLU against histones in in vitro assays and in vivo models of experimental sepsis. Measurements and Main Results: We show that CLU binds to circulating histones and reduces their inflammatory, thrombotic, and cytotoxic properties. We observed that plasma CLU levels decreased in patients with sepsis and that the decrease was greater and more durable in nonsurvivors than in survivors. Accordingly, CLU deficiency was associated with increased mortality in mouse models of sepsis and endotoxemia. Finally, CLU supplementation improved mouse survival in a sepsis model. Conclusions: This study identifies CLU as a central endogenous histone-neutralizing molecule and suggests that, in pathologies with extensive cell death, CLU supplementation may improve disease tolerance and host survival.

The effect of performance pressure and error-feedback on anxiety and performance in an interceptive task.

Introduction: Whilst the disruptive effects of anxiety on attention and performance have been well documented, the antecedents to anxiety in motivated performance scenarios are less well understood. We therefore sought to understand the cognitive appraisals that mediate the relationship between pressurised performance situations and the onset of anxiety. Methods: We tested the effects of performance pressure and error feedback on appraisals of the probability and cost of failure, the experience of anxiety, and subsequent impacts on visual attention, movement kinematics, and task performance during a virtual reality interception task. Results: A series of linear mixed effects models indicated that failure feedback and situational pressure influenced appraisals of the probability and cost of failure, which subsequently predicted the onset of anxious states. We did not, however, observe downstream effects on performance and attention. Discussion: The findings support the predictions of Attentional Control Theory Sport, that (i) momentary errors lead to negative appraisals of the probability of future failure; and (ii) that appraisals of both the cost and probability of future failure are important predictors of anxiety. The results contribute to a better understanding of the precursors to anxiety and the feedback loops that may maintain anxious states.

Investigating anionic surfactant phase diagrams using dissipative particle dynamics: development of a transferable model.

Dissipative particle dynamics (DPD) provides a powerful coarse-grained simulation technique for the study of a wide range of soft matter systems. Here, we investigate the transferability of DPD models to the prediction of anionic surfactant phase diagrams, taking advantage of fast parameter sweeps to optimise the choice of DPD parameters for these systems. Parameters are developed which provide a good representation of the phase diagrams of SDS (sodium dodecyl sulfate) and three different isomeric forms of LAS (linear alkylbenzene sulfonates) across an extensive concentration range. A high degree of transferability is seen, with parameters readily transferable to other systems, such as AES (alkyl ether sulfates). Excellent agreement is obtained with experimentally measured quantities, such as the lamellar layer spacing. Isosurfaces are produced from the surfactant head group, from which the second moment M of the isosurface normal distribution is calculated for different phase structures. Lyotropic liquid crystalline phases are characterised by a combination of the eigenvalues of M, radial distribution functions, and visual inspections.

Extracellular protein homeostasis in neurodegenerative diseases.

The protein homeostasis (proteostasis) system encompasses the cellular processes that regulate protein synthesis, folding, concentration, trafficking and degradation. In the case of intracellular proteostasis, the identity and nature of these processes have been extensively studied and are relatively well known. By contrast, the mechanisms of extracellular proteostasis are yet to be fully elucidated, although evidence is accumulating that their age-related progressive impairment might contribute to neuronal death in neurodegenerative diseases. Constitutively secreted extracellular chaperones are emerging as key players in processes that operate to protect neurons and other brain cells by neutralizing the toxicity of extracellular protein aggregates and promoting their safe clearance and disposal. Growing evidence indicates that these extracellular chaperones exert multiple effects to promote cell viability and protect neurons against pathologies arising from the misfolding and aggregation of proteins in the synaptic space and interstitial fluid. In this Review, we outline the current knowledge of the mechanisms of extracellular proteostasis linked to neurodegenerative diseases, and we examine the latest understanding of key molecules and processes that protect the brain from the pathological consequences of extracellular protein aggregation and proteotoxicity. Finally, we contemplate possible therapeutic opportunities for neurodegenerative diseases on the basis of this emerging knowledge.

Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy.

There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases.

Roles of constitutively secreted extracellular chaperones in neuronal cell repair and regeneration.

Protein quality control involves many processes that jointly act to regulate the expression, localization, turnover, and degradation of proteins, and has been highlighted in recent studies as critical to the differentiation of stem cells during regeneration. The roles of constitutively secreted extracellular chaperones in neuronal injury and disease are poorly understood. Extracellular chaperones are multifunctional proteins expressed by many cell types, including those of the nervous system, known to facilitate protein quality control processes. These molecules exert pleiotropic effects and have been implicated as playing important protective roles in a variety of stress conditions, including tissue damage, infections, and local tissue inflammation. This article aims to provide a critical review of what is currently known about the functions of extracellular chaperones in neuronal repair and regeneration and highlight future directions for this important research area. We review what is known of four constitutively secreted extracellular chaperones directly implicated in processes of neuronal damage and repair, including transthyretin, clusterin, α2-macroglobulin, and neuroserpin, and propose that investigation into the effects of these and other extracellular chaperones on neuronal repair and regeneration has the potential to yield valuable new therapies.

The Emerging Roles of Extracellular Chaperones in Complement Regulation.

The immune system is essential to protect organisms from internal and external threats. The rapidly acting, non-specific innate immune system includes complement, which initiates an inflammatory cascade and can form pores in the membranes of target cells to induce cell lysis. Regulation of protein homeostasis (proteostasis) is essential for normal cellular and organismal function, and has been implicated in processes controlling immunity and infection. Chaperones are key players in maintaining proteostasis in both the intra- and extracellular environments. Whilst intracellular proteostasis is well-characterised, the role of constitutively secreted extracellular chaperones (ECs) is less well understood. ECs may interact with invading pathogens, and elements of the subsequent immune response, including the complement pathway. Both ECs and complement can influence the progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, as well as other diseases including kidney diseases and diabetes. This review will examine known and recently discovered ECs, and their roles in immunity, with a specific focus on the complement pathway.

The Extracellular Molecular Chaperone Clusterin Inhibits Amyloid Fibril Formation and Suppresses Cytotoxicity Associated with Semen-Derived Enhancer of Virus Infection (SEVI).

Clusterin is a glycoprotein present at high concentrations in many extracellular fluids, including semen. Its increased expression accompanies disorders associated with extracellular amyloid fibril accumulation such as Alzheimer's disease. Clusterin is an extracellular molecular chaperone which prevents the misfolding and amorphous and amyloid fibrillar aggregation of a wide variety of unfolding proteins. In semen, amyloid fibrils formed from a 39-amino acid fragment of prostatic acid phosphatase, termed Semen-derived Enhancer of Virus Infection (SEVI), potentiate HIV infectivity. In this study, clusterin potently inhibited the in vitro formation of SEVI fibrils, along with dissociating them. Furthermore, clusterin reduced the toxicity of SEVI to pheochromocytoma-12 cells. In semen, clusterin may play an important role in preventing SEVI amyloid fibril formation, in dissociating SEVI fibrils and in mitigating their enhancement of HIV infection.

A Multidisciplinary Investigation into the Talent Development Processes at an English Football Academy: A Machine Learning Approach.

The talent development processes in youth football are both complex and multidimensional. The purpose of this two-fold study was to apply a multidisciplinary, machine learning approach to examine: (a) the developmental characteristics of under-9 to under-16 academy players (n = 98; Study 1), and (b) the characteristics of selected and deselected under-18 academy players (n = 18; Study 2). A combined total of 53 factors cumulated from eight data collection methods across two seasons were analysed. A cross-validated Lasso regression was implemented, using the glmnet package in R, to analyse the factors that contributed to: (a) player review ratings (Study 1), and (b) achieving a professional contract (Study 2). Results showed non-zero coefficients for improvement in subjective performance in 15 out of the 53 analysed features, with key findings revealing advanced percentage of predicted adult height (0.196), greater lob pass (0.160) and average dribble completion percentage (0.124), more total match-play hours (0.145), and an older relative age (BQ1 vs. BQ2: -0.133; BQ1 vs. BQ4: -0.060) were the most important features that contributed towards player review ratings. Moreover, PCDEQ Factor 3 and an ability to organise and engage in quality practice (PCDEQ Factor 4) were important contributing factors towards achieving a professional contract. Overall, it appears the key factors associated with positive developmental outcomes are not always technical and tactical in nature, where coaches often have their expertise. Indeed, the relative importance of these factors is likely to change over time, and with age, although psychological attributes appear to be key to reaching potential across the academy journey. The methodological techniques used here also serve as an impetus for researchers to adopt a machine learning approach when analysing multidimensional databases.