Is HIV short-sighted? Insights from a multistrain nested model

An important component of pathogen evolution at the population level is evolution within hosts. Unless evolution within hosts is very slow compared to the duration of infection, the composition of pathogen genotypes within a host is likely to change during the course of an infection, thus altering the composition of genotypes available for transmission as infection progresses. We develop a nested modeling approach that allows us to follow the evolution of pathogens at the epidemiological level by explicitly considering within-host evolutionary dynamics of multiple competing strains and the timing of transmission. We use the framework to investigate the impact of short-sighted within-host evolution on the evolution of virulence of human immunodeficiency virus (HIV), and find that the topology of the within-host adaptive landscape determines how virulence evolves at the epidemiological level. If viral reproduction rates increase significantly during the course of infection, the viral population will evolve a high level of virulence even though this will reduce the transmission potential of the virus. However, if reproduction rates increase more modestly, as data suggest, our model predicts that HIV virulence will be only marginally higher than the level that maximizes the transmission potential of the virus

Social prescribing in Greater Manchester

This report presents key findings from a mapping and research exercise undertaken by the University of Salford and Salford CVS from February to May of 2018. The research was designed to fill an important gap in our knowledge about what social prescribing activities already exist in Greater Manchester (GM), whether there exists any kind of emerging consensus around models or best practices within this GM context, and how this relates to best practices existing across the UK

The feasibility of thermal and compositional convection in Earth's inner core

Inner core convection, and the corresponding variations in grain size and alignment, has been proposed to explain the complex seismic structure of the inner core, including its anisotropy, lateral variations and the F-layer at the base of the outer core. We develop a parametrized convection model to investigate the possibility of convection in the inner core, focusing on the dominance of the plume mode of convection versus the translation mode. We investigate thermal and compositional convection separately so as to study the end-members of the system. In the thermal case the dominant mode of convection is strongly dependent on the viscosity of the inner core, the magnitude of which is poorly constrained. Furthermore recent estimates of a large core thermal conductivity result in stable thermal stratification, hindering convection. However, an unstable density stratification may arise due to the pressure dependant partition coefficient of certain light elements. We show that this unstable stratification leads to compositionally driven convection, and that inner core translation is likely to be the dominant convective mode due to the low compositional diffusivity. The style of convection resulting from a combination of both thermal and compositional effects is not easy to understand. For reasonable parameter estimates, the stabilizing thermal buoyancy is greater than the destabilizing compositional buoyancy. However we anticipate complex double diffusive processes to occur given the very different thermal and compositional diffusivities.We would like to thank Chris Davies for help with comparison to his results, plus Deputy Editor Stephane Labrosse, Renaud Deguen and ´ an anonymous reviewer for constructive comments that improved the manuscript. KHL and AD are funded by the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement number 204995. JAN is partially funded by a Royal Society University Research Fellowship.This is the final published version. This article has been accepted for publication in Geophysical Journal International ©: 2015 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved

Мовні реалії іншого часу і простору (про особливості слововживання у творах Івана Багряного)

The structure of Earthʼs deep inner core has important implications for core evolution, since it is thought to be related to the early stages of core formation. Previous studies have suggested that there exists an innermost inner core with distinct anisotropy relative to the rest of the inner core. Using an extensive new data set of handpicked absolute travel time observations of the inner core phase PKIKP, we find that the data are best explained by variations in anisotropy between two hemispheres and do not require an innermost inner core. We demonstrate that observations of an innermost inner core are an artifact from averaging over lateral anisotropy variations. More significantly we show that hemispherical variations in anisotropy, previously only imaged in the upper inner core, continue to its centre. The eastern region has 0.5–1.5% anisotropy, whereas the western region has 3.5–8.8% anisotropy increasing with depth, with a slow direction at 57–61° to the Earthʼs rotation axis at all depths. Such anisotropy is consistent with models of aligned hcp or bcc iron aggregates

Quantification of light attenuation in optically cleared mouse brains

Optical clearing, in combination with recently developed optical imaging techniques, enables visualization and acquisition of high-resolution, three-dimensional images of biological structures deep within the tissue. Many different approaches can be used to reduce light absorption and scattering within the tissue, but there is a paucity of research on the quantification of clearing efficacy. With the use of a custom-made spectroscopy system, we developed a way to quantify the quality of clearing in biological tissue and applied it to the mouse brain. Three clearing techniques were compared: BABB (1:2 mixture of benzyl alcohol and benzyl benzoate, also known as Murray’s clear), pBABB (peroxide BABB, a modification of BABB which includes the use of hydrogen peroxide), and passive CLARITY. We found that BABB and pBABB produced the highest degree of optical clearing. Furthermore, the approach allows regional measurement of light attenuation to be performed, and our results show that light is most attenuated in regions with high lipid content. We provide a way to choose between the multiple clearing protocols available, and it could prove useful for evaluating images that are acquired with cleared tissues

Bimodal imaging of inflammation with SPECT/CT and MRI using iodine-125 labeled VCAM-1 targeting microparticle conjugates

Upregulation of cell adhesion molecules on endothelial cells is a hallmark of inflammation and an early feature of several neurological conditions. Here, we describe bimodal in vivo imaging of this inflammatory event in the brain using functionalized micron-sized particles of iron oxide. The particles were conjugated to anti-VCAM-1 antibodies and subsequently labeled with iodine-125. Radiolabeling of the antibody-coated particles was straightforward and proceeded in high radiochemical yields using commercially available iodination tubes. The corresponding contrast agent was evaluated in a rat model of cerebral inflammation based on intracerebral injection of tumor necrosis factor alpha and a rat model of status epilepticus. Biodistribution studies and phosphorimaging of cryosections were used to verify in vivo imaging data obtained with single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). The contrast agent showed rapid and highly localized binding to the vasculature of inflamed brain tissue, and was effectively cleared from the blood pool within 2 min postinjection. Overall, the pattern of hypointensities observed with MRI was in good agreement with the distribution of the contrast agent as determined with SPECT and phosphorimaging; however, conspicuous differences in the signal intensities were observed. The results demonstrate that radiolabeled micron-sized particles of iron oxide enable multimodal in vivo imaging with MRI and nuclear techniques, and highlight the value of validating different imaging methods against one another

Short-sighted virus evolution and a germline hypothesis for chronic viral infections

This work was funded by The Wellcome Trust and The Royal Society grant numbers wtvm055984 (KAL) and 107653/Z/15/Z (JG), The Natural Environment Research Council grant number NE/K009524/1 (AG), and The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant number 614725-PATHPHYLODYN (OGP).With extremely short generation times and high mutability, many viruses can rapidly evolve and adapt to changing environments. This ability is generally beneficial to viruses as it allows them to evade host immune responses, evolve new behaviours, and exploit ecological niches. However, natural selection typically generates adaptation in response to the immediate selection pressures that a virus experiences in its current host. Consequently, we argue that some viruses, particularly those characterised by long durations of infection and ongoing replication, may be susceptible to short-sighted evolution, whereby a virus’ adaptation to its current host will be detrimental to its onward transmission within the host population. Here we outline the concept of short-sighted viral evolution and provide examples of how it may negatively impact viral transmission among hosts. We also propose that viruses that are vulnerable to short-sighted evolution may exhibit strategies that minimise its effects. We speculate on the various mechanisms by which this may be achieved, including viral life history strategies that result in low rates of within-host evolution, or the establishment of a ‘germline’ lineage of viruses that avoids short-sighted evolution. These concepts provide a new perspective on the way in which some viruses have been able to establish and maintain global pandemics.Publisher PDFPeer reviewe

Origins of the vagal drive controlling left ventricular contractility

The strength, functional significance and origins of direct parasympathetic innervation of the left ventricle (LV) remain controversial. In the present study we used an anaesthetized rat model to first confirm the presence of tonic inhibitory vagal influence on LV inotropy. Using genetic neuronal targeting and functional neuroanatomical mapping we tested the hypothesis that parasympathetic control of LV contractility is provided by vagal preganglionic neurones located in the dorsal motor nucleus (DVMN). It was found that under systemic β-adrenoceptor blockade (atenolol) combined with spinal cord (C1) transection (to remove sympathetic influences), intravenous administration of atropine increases LV contractility in rats anaesthetized with urethane, but not in animals anaesthetized with pentobarbital. Increased LV contractility in rats anaesthetized with urethane was also observed when DVMN neurones targeted bilaterally to express an inhibitory Drosophila allatostatin receptor were silenced by application of an insect peptide allatostatin. Microinjections of glutamate and muscimol to activate or inhibit neuronal cell bodies in distinct locations along the rostro-caudal extent of the left and right DVMN revealed that vagal preganglionic neurones which have an impact on LV contractility are located in the caudal region of the left DVMN. Changes in LV contractility were only observed when this subpopulation of DVMN neurones was activated or inhibited. These data confirm the existence of a tonic inhibitory muscarinic influence on LV contractility. Activity of a subpopulation of DVMN neurones provides functionally significant parasympathetic control of LV contractile function. This article is protected by copyright. All rights reserved

Flow-Based Single Cell Deposition for High-Throughput Screening of Protein Libraries

The identification and engineering of proteins having refined or novel characteristics is an important area of research in many scientific fields. Protein modelling has enabled the rational design of unique proteins, but high-throughput screening of large libraries is still required to identify proteins with potentially valuable properties. Here we report on the development and evaluation of a novel fluorescent activated cell sorting based screening platform. Single bacterial cells, expressing a protein library to be screened, are electronically sorted and deposited onto plates containing solid nutrient growth media in a dense matrix format of between 44 and 195 colonies/cm2. We show that this matrix format is readily applicable to machine interrogation (<30 seconds per plate) and subsequent bioinformatic analysis (~60 seconds per plate) thus enabling the high-throughput screening of the protein library. We evaluate this platform and show that bacteria containing a bioluminescent protein can be spectrally analysed using an optical imager, and a rare clone (0.5% population) can successfully be identified, picked and further characterised. To further enhance this screening platform, we have developed a prototype electronic sort stream multiplexer, that when integrated into a commercial flow cytometric sorter, increases the rate of colony deposition by 89.2% to 24 colonies per second. We believe that the screening platform described here is potentially the foundation of a new generation of high-throughput screening technologies for proteins