Critical information gaps remain in understanding impacts of industrial seismic surveys on marine vertebrates

This is the final version. Available from Inter Research via the DOI in this record. Anthropogenic noise is increasing throughout the world's oceans. One major contributor is industrial seismic surveys-a process typically undertaken to locate and estimate the quantity of oil and gas deposits beneath the seafloor-which, in recent years, has increased in magnitude and scope in some regions. Regulators permit this activity despite widespread uncertainties regarding the potential ecological impacts of seismic surveys and gaps in baseline information on some key species of conservation concern. Research to date suggests that impacts vary, from displacement to direct mortality, but these effects remain poorly understood for most species. Here, we summarize potential effects of seismic surveys, describe key knowledge gaps, and recommend broad-scale research priorities for 3 impacted taxonomic groups: fish, marine mammals, and sea turtles. We also suggest further technological advances, improved mitigation measures, and better policy and management structures to minimize the ecological impacts of seismic surveys in light of scientific uncertainty.Natural Environment Research Counci

A log-likelihood-gain intensity target for crystallographic phasing that accounts for experimental error

The crystallographic diffraction experiment measures Bragg intensities; crystallographic electron-density maps and other crystallographic calculations in phasing require structure-factor amplitudes. If data were measured with no errors, the structure-factor amplitudes would be trivially proportional to the square roots of the intensities. When the experimental errors are large, and especially when random errors yield negative net intensities, the conversion of intensities and their error estimates into amplitudes and associated error estimates becomes nontrivial. Although this problem has been addressed intermittently in the history of crystallographic phasing, current approaches to accounting for experimental errors in macromolecular crystallography have numerous significant defects. These have been addressed with the formulation of LLGI, a log-likelihood-gain function in terms of the Bragg intensities and their associated experimental error estimates. LLGI has the correct asymptotic behaviour for data with large experimental error, appropriately downweighting these reflections without introducing bias. LLGI abrogates the need for the conversion of intensity data to amplitudes, which is usually performed with the French and Wilson method [French & Wilson (1978), Acta Cryst. A35, 517-525], wherever likelihood target functions are required. It has general applicability for a wide variety of algorithms in macromolecular crystallography, including scaling, characterizing anisotropy and translational noncrystallographic symmetry, detecting outliers, experimental phasing, molecular replacement and refinement. Because it is impossible to reliably recover the original intensity data from amplitudes, it is suggested that crystallographers should always deposit the intensity data in the Protein Data Bank.This research was supported by the Wellcome Trust (Principal Research Fellowship to RJR, grant 082961/Z/07/Z). The Cambridge Institute for Medical Research is supported by a Wellcome Trust Strategic Award (100140)

Law, ethics and end-of-life care: the policy and practice interface in England

No abstrac

Effects of footwear variations on three-dimensional kinematics and tibial accelerations of specific movements in American football

American football is associated with a high rate of non-contact chronic injuries. Players are able to select from both high and low cut footwear. The aim of the current investigation was to examine the influence of high and low cut American football specific footwear on tibial accelerations and three-dimensional (3D) kinematics during three sport specific movements. Twelve male American football players performed three movements, run, cut and vertical jump whilst wearing both low and high cut footwear. 3D kinematics of the lower extremities were measured using an eight-camera motion analysis system alongside tibial acceleration parameters which were obtained using a shank mounted accelerometer. Tibial acceleration and 3D kinematic differences between the different footwear were examined using either repeated measures or Friedman’s ANOVA. Tibial accelerations were significantly greater in the low cut footwear in comparison to the high cut footwear for the run and cut movements. In addition, peak ankle eversion and tibial internal rotation parameters were shown to be significantly greater in the low cut footwear in the running and cutting movement conditions. The current study indicates that the utilization of low cut American football footwear for training/performance may place American footballers at increased risk from chronic injuries

From mental health policy development in Ghana to implementation: What are the barriers?

Objective: This paper identifies the key barriers to mental health policy implementation in Ghana and suggests ways of overcoming them. Method: The study used both quantitative and qualitative methods. Quantitatively, the WHO Mental Health Policy and Plan Checklist and the WHO Mental Health Legislation Checklist were employed to analyse the content of mental health policy, plans and legislation in Ghana. Qualitative data was gathered using in-depth interviews and focus group discussions with key stakeholders in mental health at the macro, meso and micro levels. These were used to identify barriers to the implementation of mental health policy, and steps to overcoming these. Results: Barriers to mental health policy implementation identified by participants include: low priority and lack of political commitment to mental health; limited human and financial resources; lack of intersectoral collaboration and consultation; inadequate policy dissemination; and an absence of research-based evidence to inform mental health policy. Suggested steps to overcoming the barriers include: revision of mental health policy and legislation; training and capacity development and wider consultation. Conclusion: These results call for well-articulated plans to address the barriers to the implementation of mental health policy in Ghana to reduce the burden associated with mental disorders.Key Words: Mental health; Policy; Implementation; Barriers; Legislatio

Enabling rational gut microbiome manipulations by understanding gut ecology through experimentally-evidenced in silico models

© 2021 The Author(s). The gut microbiome has emerged as a contributing factor in non-communicable disease, rendering it a target of health-promoting interventions. Yet current understanding of the host-microbiome dynamic is insufficient to predict the variation in intervention outcomes across individuals. We explore the mechanisms that underpin the gut bacterial ecosystem and highlight how a more complete understanding of this ecology will enable improved intervention outcomes. This ecology varies within the gut over space and time. Interventions disrupt these processes, with cascading consequences throughout the ecosystem. In vivo studies cannot isolate and probe these processes at the required spatiotemporal resolutions, and in vitro studies lack the representative complexity required. However, we highlight that, together, both approaches can inform in silico models that integrate cellular-level dynamics, can extrapolate to explain bacterial community outcomes, permit experimentation and observation over ecological processes at high spatiotemporal resolution, and can serve as predictive platforms on which to prototype interventions. Thus, it is a concerted integration of these techniques that will enable rational targeted manipulations of the gut ecosystem.University of Sydney’s Centre for Advanced Food and Engineering; JPMO acknowledges a PhD scholarship from the Faculty of Engineering at the University of Sydney. ERS acknowledges the financial support from the à Beckett Cancer Research Trust (University of Sydney Fellowship)

Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

Ab initio solution of macromolecular crystal structures without direct methods

The majority of macromolecular crystal structures are determined using the method of molecular replacement, in which known related structures are rotated and translated to provide an initial atomic model for the new structure. A theoretical understanding of the signal-to-noise ratio in likelihood-based molecular replacement searches has been developed to account for the influence of model quality and completeness, as well as the resolution of the diffraction data. Here we show that, contrary to current belief, molecular replacement need not be restricted to the use of models comprising a substantial fraction of the unknown structure. Instead, likelihood-based methods allow a continuum of applications depending predictably on the quality of the model and the resolution of the data. Unexpectedly, our understanding of the signal-to-noise ratio in molecular replacement leads to the finding that, with data to sufficiently high resolution, fragments as small as single atoms of elements usually found in proteins can yield ab initio solutions of macromolecular structures, including some that elude traditional direct methods.This research was supported by a Principal Research Fellowship from the Wellcome Trust (082961/Z/07/Z to R.J.R.), and grants from the NIH (Grant P01GM063210 to R.J.R.), the Swedish Research Council (Grant 521-2014-1833 to K.T. and Grant 2007-5648 to B.L.), the Knut and Alice Wallenberg Foundation (K.T.), the Novo Nordisk Foundation (K.T.), and the Röntgen Ångström Cluster (Grant 349-2013-597 to B.L.). The research was facilitated by Wellcome Trust Strategic Award 100140 to the Cambridge Institute for Medical Research

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

This is the final version of the article. Available from American Society for Clinical Investigation via the DOI in this record.The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.ABT, AC, and PMS received funding from a Wellcome Trust Collaborative Award (201529/Z/16/Z). ABT, SJB, AJB, and TMH were funded through a Medical Research Council programme leader grant provided by the MRC Toxicology Unit. CCF, LMB, AJM, and HES were funded by the Eli Lilly Company. JMB received funding through a Lilly Research Award Program (LRAP) grant (Eli Lilly). RP received funding from the Marie Curie grant “Extrabrain” (European Commission). AC is a senior principal research fellow and PMS a principal research fellow of the National Health and Medical Research Council of Australia. Tissue samples were from Randy Woltjer at the Oregon Alzheimer’s Disease Center. The Oregon Alzheimer’s Disease Center is supported by NIH grant P30AG008017

Interface Effects on Attenuation and Phase Velocities in Metal-Matrix Composites

One often determines the effective elastic moduli and damping of a heterogeneous material by using elastic waves (propagating or standing). Several theoretical studies show that for long wavelengths one can calculate the effective wave speeds of plane longitudinal and shear waves through a composite material. At long wavelengths the wave speeds thus calculated are nondispersive and hence provide the values for the static effective elastic properties. References to some of the recent theoretical and experimental studies can be found in [1–12]. The scattering formulations developed in [1–8] provide a means to obtain both the effective wave speeds and the damping caused by scattering