Risk, precaution and science: towards a more constructive policy debate. Talking point on the precautionary principle

Few issues in contemporary risk policy are as momentous or contentious as the precautionary principle. Since it first emerged in German environmental policy, it has been championed by environmentalists and consumer protection groups, and resisted by the industries they oppose (Raffensperger & Tickner, 1999). Various versions of the principle now proliferate across different national and international jurisdictions and policy areas (Fisher, 2002). From a guiding theme in European Commission (EC) environmental policy, it has become a general principle of EC law (CEC, 2000; Vos & Wendler, 2006). Its influence has extended from the regulation of environmental, technological and health risks to the wider governance of science, innovation and trade (O'Riordan & Cameron, 1994)

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed and immunomodulated patients. Initial infection with JCPyV is common and the virus establishes a long-term persistent infection in the urogenital system of 50-70% of the human population worldwide. A major gap in the field is that we do not know how the virus traffics from the periphery to the brain to cause disease. Our recent discovery that human choroid plexus epithelial cells are fully susceptible to virus infection together with reports of JCPyV infection of choroid plexus in vivo has led us to hypothesize that the choroid plexus plays a fundamental role in this process. The choroid plexus is known to relay information between the blood and the brain by the release of extracellular vesicles. This is particularly important because human macroglia (oligodendrocytes and astrocytes), the major targets of virus infection in the central nervous system (CNS), do not express the known attachment receptors for the virus and do not bind virus in human tissue sections. In this report we show that JCPyV infected choroid plexus epithelial cells produce extracellular vesicles that contain JCPyV and readily transmit the infection to human glial cells. Transmission of the virus by extracellular vesicles is independent of the known virus attachment receptors and is not neutralized by antisera directed at the virus. We also show that extracellular vesicles containing virus are taken into target glial cells by both clathrin dependent endocytosis and macropinocytosis. Our data support the hypothesis that the choroid plexus plays a fundamental role in the dissemination of virus to brain parenchyma

Reading Videogames as (authorless) Literature

This article presents the outcomes of research, funded by the Arts and Humanities Research Council in England and informed by work in the fields of new literacy research, gaming studies and the socio-cultural framing of education, for which the videogame L.A. Noire (Rockstar Games, 2011) was studied within the orthodox framing of the English Literature curriculum at A Level (pre-University) and Undergraduate (degree level). There is a plethora of published research into the kinds of literacy practices evident in videogame play, virtual world engagement and related forms of digital reading and writing (Gee, 2003; Juul, 2005; Merchant, Gillen, Marsh and Davies, 2012; Apperley and Walsh, 2012; Bazalgette and Buckingham, 2012) as well as the implications of such for home / school learning (Dowdall, 2006; Jenkins, 2006; Potter, 2012) and for teachers’ own digital lives (Graham, 2012). Such studies have tended to focus on younger children and this research is also distinct from such work in the field in its exploration of the potential for certain kinds of videogame to be understood as 'digital transformations' of conventional ‘schooled’ literature. The outcomes of this project raise implications of such a conception for a further implementation of a ‘reframed’ literacy (Marsh, 2007) within the contemporary curriculum of a traditional and conservative ‘subject’. A mixed methods approach was adopted. Firstly, students contributing to a gamplay blog requiring them to discuss their in-game experience through the ‘language game’ of English Literature, culminating in answering a question constructed with the idioms of the subject’s set text ‘final examination’. Secondly, students taught their teachers to play L.A. Noire, with free choice over the context for this collaboration. Thirdly, participants returned to traditional roles in order to work through a set of study materials provided, designed to reproduce the conventions of the ‘study guide’ for literature education. Interviews were conducted after each phase and the outcomes informed a redrafting of the study materials which are now available online for teachers – this being the ‘practical’ outcome of the research (Berger and McDougall, 2012). In the act of inserting the study of L.A. Noire into the English Literature curriculum as currently framed, this research moves, through a practical ‘implementation’ beyond longstanding debates around narratology and ludology (Frasca, 2003; Juul, 2005) in the field of game studies (Leaning, 2012) through a direct connection to new literacy studies and raises epistemological questions about ‘subject identity’, informed by Bernstein (1996) and Bourdieu (1986) and the implications for digital transformations of texts for both ideas about cultural value in schooled literacy (Kendall and McDougall, 2011) and the politics of ‘expertise’ in pedagogic relations (Ranciere, 2009, Bennett, Kendall and McDougall, 2012a)

Biogenesis of JC Polyomavirus Associated Extracellular Vesicles

JC polyomavirus (JCPyV) is a small, non-enveloped virus that persists in the kidney in about half the adult population. In severely immune-compromised individuals JCPyV causes the neurodegenerative disease progressive multifocal leukoencephalopathy (PML) in the brain. JCPyV has been shown to infect cells by both direct and indirect mechanisms, the latter involving extracellular vesicle (EV) mediated infection. While direct mechanisms of infection are well studied indirect EV mediated mechanisms are poorly understood. Using a combination of chemical and genetic approaches we show that several overlapping intracellular pathways are responsible for the biogenesis of virus containing EV. Here we show that targeting neutral sphingomyelinase 2 (nSMase2) with the drug cambinol decreased the spread of JCPyV over several viral life cycles. Genetic depletion of nSMase2 by either shRNA or CRISPR/Cas9 reduced EV-mediated infection. Individual knockdown of seven ESCRT-related proteins including HGS, ALIX, TSG101, VPS25, VPS20, CHMP4A, and VPS4A did not significantly reduce JCPyV associated EV (JCPyV(+) EV) infectivity, whereas knockdown of the tetraspanins CD9 and CD81 or trafficking and/or secretory autophagy-related proteins RAB8A, RAB27A, and GRASP65 all significantly reduced the spread of JCPyV and decreased EV-mediated infection. These findings point to a role for exosomes and secretory autophagosomes in the biogenesis of JCPyV associated EVs with specific roles for nSMase2, CD9, CD81, RAB8A, RAB27A, and GRASP65 proteins

Boundary lubrication properties of materials with expansive freezing

We have performed molecular dynamics simulations of solid-solid contacts lubricated by a model fluid displaying many of the properties of water, particularly its expansive freezing. Near the region where expansive freezing occurs, the lubricating film remains fluid, and the friction force decreases linearly as the shear velocity is reduced. No sign of stick-slip motion is observed even at the lowest velocities. We give a simple interpretation of these results, and suggest that in general good boundary lubrication properties will be found in the family of materials with expansive freezing.Comment: Version to appear in Phys. Rev. Let

JC Polyomavirus Uses Extracellular Vesicles To Infect Target Cells

The endemic human JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy in immune-suppressed patients. The mechanisms of virus infection in vivo are not understood because the major target cells for virus in the brain do not express virus receptors and do not bind virus. We found that JCPyV associates with extracellular vesicles (EVs) and can infect target cells independently of virus receptors. Virus particles were found packaged inside extracellular vesicles and attached to the outer side of vesicles. Anti-JCPyV antisera reduced infection by purified virus but had no effect on infection by EV-associated virus. Treatment of cells with the receptor-destroying enzyme neuraminidase inhibited infection with purified virus but did not inhibit infection by EV-associated virus. Mutant pseudoviruses defective in sialic acid receptor binding could not transduce cells as purified pseudovirions but could do so when associated with EVs. This alternative mechanism of infection likely plays a critical role in the dissemination and spread of JCPyV both to and within the central nervous system

The PDZ domain of the SpoIVB serine peptidase facilitates multiple functions

During spore formation in Bacillus subtilis, the SpoIVB protein is a critical component of the sigma (K) regulatory checkpoint. SpoIVB has been shown to be a serine peptidase that is synthesized in the spore chamber and which self-cleaves, releasing active forms. These forms can signal proteolytic processing of the transcription factor sigma (K) in the outer mother cell chamber of the sporulating cell. This forms the basis of the sigma (K) checkpoint and ensures accurate sigma (K)-controlled gene expression. SpoIVB has also been shown to activate a second distinct process, termed the second function, which is essential for the formation of heat-resistant spores. In addition to the serine peptidase domain, SpoIVB contains a PDZ domain. We have altered a number of conserved residues in the PDZ domain by site-directed mutagenesis and assayed the sporulation phenotype and signaling properties of mutant SpoIVB proteins. Our work has revealed that the SpoIVB PDZ domain could be used for up to four distinct processes, (i) targeting of itself for trans proteolysis, (11) binding to the protease inhibitor BofC, (iii) signaling of pro-sigma (K) processing, and (iv) signaling of the second function of SpoIVB

From the cell membrane to the nucleus: unearthing transport mechanisms for Dynein

Mutations in the motor protein cytoplasmic dynein have been found to cause Charcot-Marie-Tooth disease, spinal muscular atrophy, and severe intellectual disabilities in humans. In mouse models, neurodegeneration is observed. We sought to develop a novel model which could incorporate the effects of mutations on distance travelled and velocity. A mechanical model for the dynein mediated transport of endosomes is derived from first principles and solved numerically. The effects of variations in model parameter values are analysed to find those that have a significant impact on velocity and distance travelled. The model successfully describes the processivity of dynein and matches qualitatively the velocity profiles observed in experiments

Time-Resolved Studies of Stick-Slip Friction in Sheared Granular Layers

Sensitive and fast force measurements are performed on sheared granular layers undergoing stick-slip motion, along with simultaneous imaging. A full study has been done for spherical particles with a +-20% size distribution. Stick-slip motion due to repetitive fluidization of the layer occurs for low driving velocities. Between major slip events, slight creep occurs that is variable from one event to the next. The effects of changing the stiffness k and velocity V of the driving system are studied in detail. The stick-slip motion is almost periodic for spherical particles over a wide range of parameters, but becomes irregular when k is large and V is relatively small. At larger V, the motion becomes smoother and is affected by the inertia of the upper plate bounding the layer. Measurements of the period T and amplitude A of the relative motion are presented as a function of V. At a critical value Vc, a transition to continuous sliding motion occurs that is discontinuous for k not too large. The time dependence of the instantaneous velocity of the upper plate and the frictional force produced by the granular layer are determined within individual slipping events. The force is a multi-valued function of the instantaneous velocity, with pronounced hysteresis and a sudden drop prior to resticking. Measurements of vertical displacement reveal a small dilation of the material (about one tenth of the mean particle size in a layer 20 particles deep) associated with each slip event. Finally, optical imaging reveals that localized microscopic rearrangements precede (and follow) each slip event. The behavior of smooth particles is contrasted with that of rough particles.Comment: 20, pages, 17 figures, to appear in Phys. Rev.