Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity

A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world. Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.     

Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia.

Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait.     

An ancient nova shell around the dwarf nova Z Camelopardalis

Cataclysmic variables (classical novae and dwarf novae) are binary star systems in which a red dwarf transfers hydrogen-rich matter, by way of an accretion disk, to its white dwarf companion. In dwarf novae, an instability is believed to episodically dump much of the accretion disk onto the white dwarf. The liberation of gravitational potential energy then brightens these systems by up to 100-fold every few weeks or months. Thermonuclear-powered eruptions thousands of times more luminous occur in classical novae, accompanied by significant mass ejection and formation of clearly visible shells from the ejected material. Theory predicts that the white dwarfs in all dwarf novae must eventually accrete enough mass to undergo classical nova eruptions. Here we report a shell, an order of magnitude more extended than those detected around many classical novae, surrounding the prototypical dwarf nova Z Camelopardalis. The derived shell mass matches that of classical novae, and is inconsistent with the mass expected from a dwarf nova wind or a planetary nebula. The shell observationally links the prototypical dwarf nova Z Camelopardalis with an ancient nova eruption and the classical nova process.     

Improving Forecast of Binary Rare Events Data: A GAM‐Based Approach

This paper develops a method for modelling binary response data in a regression model with highly unbalanced class sizes. When the class sizes are highly unbalanced and the minority class represents a rare event, conventional regression analysis, i.e. logistic regression models, could underestimate the probability of the rare event. To overcome this drawback, we introduce a flexible skewed link function based on the quantile function of the generalized extreme value (GEV) distribution in a generalized additive model (GAM). The proposed model is known as generalized extreme value additive (GEVA) regression model, and a modified version of the local scoring algorithm is suggested to estimate it. We apply the proposed model to a dataset on Italian small and medium enterprises (SMEs) to estimate the default probability of SMEs. Our proposal performs better than the logistic (linear or additive) model in terms of predictive accuracy. Copyright © 2015 John Wiley & Sons, Ltd.     

Complexity Management,Democracy and Social Consciousness: Challenges for an Evolutionary Learning Society

Most of the recent approaches to support evolutionary learning communities have offered tools to support agreements on a shared vision. Few have explained how to effectively implement the agreed actions from such a shared vision. From a cybernetic perspective, the present paper explains why the development of structural conditions for democratic involvement is a necessary condition for the effective implementation of evolutionary development at the societal level. It offers insights from cybernetic theory on how to encourage increased participation and social consciousness. Finally, it presents an example of how to design and develop local Agoras, following these criteria. Roger Harnden is an independent researcher.     

Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis

Widespread demyelination and axonal loss are the pathological hallmarks of multiple sclerosis. The multifocal nature of this chronic inflammatory disease of the central nervous system complicates cellular therapy and puts emphasis on both the donor cell origin and the route of cell transplantation. We established syngenic adult neural stem cell cultures and injected them into an animal model of multiple sclerosis--experimental autoimmune encephalomyelitis (EAE) in the mouse--either intravenously or intracerebroventricularly. In both cases, significant numbers of donor cells entered into demyelinating areas of the central nervous system and differentiated into mature brain cells. Within these areas, oligodendrocyte progenitors markedly increased, with many of them being of donor origin and actively remyelinating axons. Furthermore, a significant reduction of astrogliosis and a marked decrease in the extent of demyelination and axonal loss were observed in transplanted animals. The functional impairment caused by EAE was almost abolished in transplanted mice, both clinically and neurophysiologically. Thus, adult neural precursor cells promote multifocal remyelination and functional recovery after intravenous or intrathecal injection in a chronic model of multiple sclerosis.