Persistence of scrapie infectivity within a farm environment after cleaning and decontamination

Scrapie of sheep/goats and Chronic Wasting Disease (CWD) of deer/elk are contagious prion diseases where environmental reservoirs are directly implicated in the transmission of disease. In this study the effectiveness of recommended scrapie farm decontamination regimes was evaluated by a sheep bioassay using buildings naturally contaminated with scrapie. Pens within a farm building were treated with either 20,000ppm free chorine solution for one hour, or were treated to same but were followed with painting and full re-galvanisation or replacement of metalwork within the pen. Scrapie susceptible lambs of the PRNP genotype VRQ/VRQ were reared within these pens and their scrapie status was monitored by RAMALT. All animals became infected over an 18-month period, even in the pen that had been subject to the most stringent decontamination process. This data suggests that recommended current guidelines for the decontamination of farm buildings following outbreaks of scrapie do little to reduce the titre of infectious scrapie material and that environmental re-contamination could also be an issue associated with these premises

Circulation of prions within dust on a scrapie affected farm

Prion diseases are fatal neurological disorders that affect humans and animals. Scrapie of sheep/goats and Chronic Wasting Disease (CWD) of deer/elk are contagious prion diseases where environmental reservoirs have a direct link to the transmission of disease. Using protein misfolding cyclic amplification we demonstrate that scrapie PrPSc can be detected within circulating dusts that are present on a farm that is naturally contaminated with sheep scrapie. The presence of infectious scrapie within airborne dusts may represent a possible route of infection and illustrates the difficulties that may be associated with the effective decontamination of such scrapie affected premises

Objects in contact with classical scrapie sheep act as a reservoir for scrapie transmission

Classical scrapie is an environmentally transmissible prion disease of sheep and goats. Prions can persist and remain potentially infectious in the environment for many years and thus pose a risk of infecting animals after re-stocking. In vitro studies using serial protein misfolding cyclic amplification (sPMCA) have suggested that objects on a scrapie- affected sheep farm could contribute to disease transmission. This in vivo study aimed to determine the role of field furniture (water troughs, feeding troughs, fencing, and other objects that sheep may rub against) used by a scrapie-infected sheep flock as a vector for disease transmission to scrapie-free lambs with the prion protein genotype VRQ/VRQ, which is associated with high susceptibility to classical scrapie. When the field furniture was placed in clean accommodation, sheep became infected when exposed to either a water trough (four out of five) or to objects used for rubbing (four out of seven). This field furniture had been used by the scrapie-infected flock 8 weeks earlier and had previously been shown to harbor scrapie prions by sPMCA. Sheep also became infected (20 out of 23) through exposure to contaminated field furniture placed within pasture not used by scrapie-infected sheep for 40 months, even though swabs from this furniture tested negative by PMCA. This infection rate decreased (1 out of 12) on the same paddock after replacement with clean field furniture. Twelve grazing sheep exposed to field furniture not in contact with scrapie-infected sheep for 18 months remained scrapie free. The findings of this study highlight the role of field furniture used by scrapie-infected sheep to act as a reservoir for disease re-introduction although infectivity declines considerably if the field furniture has not been in contact with scrapie-infected sheep for several months. PMCA may not be as sensitive as VRQ/VRQ sheep to test for environmental contamination

Durability and inflammogenic impact of carbon nanotubes compared with asbestos fibres

<p>Abstract</p> <p>Background</p> <p>It has been suggested that carbon nanotubes might conform to the fibre pathogenicity paradigm that explains the toxicities of asbestos and other fibres on a continuum based on length, aspect ratio and biopersistence. Some types of carbon nanotubes satisfy the first two aspects of the fibre paradigm but only recently has their biopersistence begun to be investigated. Biopersistence is complex and requires <it>in vivo </it>testing and analysis. However durability, the chemical mimicking of the process of fibre dissolution using <it>in vitro </it>treatment, is closely related to biopersistence and more readily determined. Here, we describe an experimental process to determine the durability of four types of carbon nanotubes in simulated biological fluid (Gambles solution), and their subsequent pathogenicity <it>in vivo </it>using a mouse model sensitive to inflammogenic effects of fibres. The <it>in vitro </it>and <it>in vivo </it>results were compared with well-characterised glass wool and asbestos fibre controls.</p> <p>Results</p> <p>After incubation for up to 24 weeks in Gambles solution, our control fibres were recovered at percentages consistent with their known <it>in vitro </it>durabilities and/or <it>in vivo </it>persistence, and three out of the four types of carbon nanotubes tested (single-walled (CNT_SW) and multi-walled (CNT_TANG2, CNT_SPIN)) showed no, or minimal, loss of mass or change in fibre length or morphology when examined by electron microscopy. However, the fourth type [multi-walled (CNT_LONG1)] lost 30% of its original mass within the first three weeks of incubation, after which there was no further loss. Electron microscopy of CNT_LONG1samples incubated for 10 weeks confirmed that the proportion of long fibres had decreased compared to samples briefly exposed to the Gambles solution. This loss of mass and fibre shortening was accompanied by a loss of pathogenicity when injected into the peritoneal cavities of C57Bl/6 mice compared to fibres incubated briefly. CNT_SWdid not elicit an inflammogenic effect in the peritoneal cavity assay used here.</p> <p>Conclusions</p> <p>These results support the view that carbon nanotubes are generally durable but may be subject to bio-modification in a sample-specific manner. They also suggest that pristine carbon nanotubes, either individually or in rope-like aggregates of sufficient length and aspect ratio, can induce asbestos-like responses in mice, but that the effect may be mitigated for certain types that are less durable in biological systems. Results indicate that durable carbon nanotubes that are either short or form tightly bundled aggregates with no isolated long fibres are less inflammogenic in fibre-specific assays.</p

The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

Background: Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results: Single nucleotide variants (P = 7.0 × 10–03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10–06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10–05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10–09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions: Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches

Robots for Humanity: Using Assistive Robots to Empower People with Disabilities

Assistive mobile manipulators have the potential to one day serve as surrogates and helpers for people with disabilities, giving them the freedom to perform tasks such as scratching an itch, picking up a cup, or socializing with their families. This article introduces a collaborative project with the goal of putting assistive mobile manipulators into real homes to work with people with disabilities. Through a participatory design process in which users have been actively involved from day one, we are identifying and developing assistive capabilities for the PR2 robot. Our approach is to develop a diverse suite of open source software tools that blend the capabilities of the user and the robot. Within this article, we introduce the project, describe our progress, and discuss lessons we have learned.This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by IEEE-Institute of Electrical and Electronics Engineers and can be found at: http://ieeexplore.ieee.org/xpl/RecentIssue.jsp?punumber=100. ©2013 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other users, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works for resale or redistribution to servers or lists, or reuse of any copyrighted components of this work in other works.Keywords: Medical robotics, Biomedical equipment, Robots, Control systems, Handicapped aids, Software development, Exoskeletons, Sensory aids, Human factors, Prosthetic

Matter-wave Atomic Gradiometer Interferometric Sensor (MAGIS-100)

MAGIS-100 is a next-generation quantum sensor under construction at Fermilab that aims to explore fundamental physics with atom interferometry over a 100-meter baseline. This novel detector will search for ultralight dark matter, test quantum mechanics in new regimes, and serve as a technology pathfinder for future gravitational wave detectors in a previously unexplored frequency band. It combines techniques demonstrated in state-of-the-art 10-meter-scale atom interferometers with the latest technological advances of the world's best atomic clocks. MAGIS-100 will provide a development platform for a future kilometer-scale detector that would be sufficiently sensitive to detect gravitational waves from known sources. Here we present the science case for the MAGIS concept, review the operating principles of the detector, describe the instrument design, and study the detector systematics.Comment: 65 pages, 18 figure

A global phylogeny of butterflies reveals their evolutionary history, ancestral hosts and biogeographic origins

Butterflies are a diverse and charismatic insect group that are thought to have evolved with plants and dispersed throughout the world in response to key geological events. However, these hypotheses have not been extensively tested because a comprehensive phylogenetic framework and datasets for butterfly larval hosts and global distributions are lacking. We sequenced 391 genes from nearly 2,300 butterfly species, sampled from 90 countries and 28 specimen collections, to reconstruct a new phylogenomic tree of butterflies representing 92% of all genera. Our phylogeny has strong support for nearly all nodes and demonstrates that at least 36 butterfly tribes require reclassification. Divergence time analyses imply an origin similar to 100 million years ago for butterflies and indicate that all but one family were present before the K/Pg extinction event. We aggregated larval host datasets and global distribution records and found that butterflies are likely to have first fed on Fabaceae and originated in what is now the Americas. Soon after the Cretaceous Thermal Maximum, butterflies crossed Beringia and diversified in the Palaeotropics. Our results also reveal that most butterfly species are specialists that feed on only one larval host plant family. However, generalist butterflies that consume two or more plant families usually feed on closely related plants

Directed Evolution Generates a Novel Oncolytic Virus for the Treatment of Colon Cancer

Background Viral-mediated oncolysis is a novel cancer therapeutic approach with the potential to be more effective and less toxic than current therapies due to the agents selective growth and amplification in tumor cells. To date, these agents have been highly safe in patients but have generally fallen short of their expected therapeutic value as monotherapies. Consequently, new approaches to generating highly potent oncolytic viruses are needed. To address this need, we developed a new method that we term “Directed Evolution” for creating highly potent oncolytic viruses. Methodology/Principal Findings Taking the “Directed Evolution” approach, viral diversity was increased by pooling an array of serotypes, then passaging the pools under conditions that invite recombination between serotypes. These highly diverse viral pools were then placed under stringent directed selection to generate and identify highly potent agents. ColoAd1, a complex Ad3/Ad11p chimeric virus, was the initial oncolytic virus derived by this novel methodology. ColoAd1, the first described non-Ad5-based oncolytic Ad, is 2–3 logs more potent and selective than the parent serotypes or the most clinically advanced oncolytic Ad, ONYX-015, in vitro. ColoAd1's efficacy was further tested in vivo in a colon cancer liver metastasis xenograft model following intravenous injection and its ex vivo selectivity was demonstrated on surgically-derived human colorectal tumor tissues. Lastly, we demonstrated the ability to arm ColoAd1 with an exogenous gene establishing the potential to impact the treatment of cancer on multiple levels from a single agent. Conclusions/Significance Using the “Directed Evolution” methodology, we have generated ColoAd1, a novel chimeric oncolytic virus. In vitro, this virus demonstrated a &gt;2 log increase in both potency and selectivity when compared to ONYX-015 on colon cancer cells. These results were further supported by in vivo and ex vivo studies. Furthermore, these results have validated this methodology as a new general approach for deriving clinically-relevant, highly potent anti-cancer virotherapies

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials