52 research outputs found

    Epidermal growth factor targeting of bacteriophage to the choroid plexus for gene delivery to the central nervous system via cerebrospinal fluid

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    Because the choroid plexus normally controls the production and composition of cerebrospinal fluid and, as such, its many functions of the central nervous system, we investigated whether ligand-mediated targeting could deliver genes to its secretory epithelium. We show here that when bacteriophages are targeted with epidermal growth factor, they acquire the ability to enter choroid epithelial cells grown in vitro as cell cultures, ex vivo as tissue explants or in vivo by intracerebroventricular injection. The binding and internalization of these particles activate EGF receptors on targeted cells, and the dose- and time-dependent internalization of particles is inhibited by the presence of excess ligand. When the phage genome is further reengineered to contain like green fluorescent protein or firefly luciferase under control of the cytomegalovirus promoter, gene expression is detectable in the choroid plexus and ependymal epithelium by immunohistochemistry or by noninvasive imaging, respectively. Taken together, these data support the hypothesis that reengineered ligand-mediated gene delivery should be considered a viable strategy to increase the specificity of gene delivery to the central nervous system and bypass the blood-brain barrier so as to exploit the biological effectiveness of the choroid plexus as a portal of entry into the brain

    Persecutory delusions: Effects of cognitive bias modification for interpretation and the Maudsley Review Training Programme on social anxiety, jumping to conclusions, belief inflexibility and paranoia

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    Background and objectives: The Threat Anticipation Model (Freeman, 2007) implicates social anxiety, jumping to conclusions (JTC) and belief inflexibility in persecutory delusions. We investigated whether Cognitive Bias Modification for Interpretation (CBM-I; Turner et al., 2011) improves social anxiety by targeting negative interpretation bias of ambiguous social information. We determined whether the Maudsley Review Training Programme (MRTP; Waller et al., 2011) improves JTC, belief inflexibility and paranoia. We also explored effects of CBM-I on JTC/belief inflexibility and paranoia, as well as the MRTP on social anxiety. Methods: Twelve participants from Early Intervention and Recovery Services in East Anglia completed measures of social anxiety, paranoia, JTC and belief inflexibility. A concurrent multiple baseline case series design was used. Results: Three of twelve participants improved in social anxiety following CBM-I, paranoia improved in 6/12 cases. CBM-I had no effect on JTC/belief inflexibility. The MRTP improved JTC and/or belief inflexibility in 9/12 cases, while improving paranoia for 6/12 individuals. The MRTP improved social anxiety in one case. Limitations: The small sample size and large effects necessary for single case series designs limit the generality of findings. These are discussed in more detail. Conclusions: This study suggests that whilst both CBM-I and the MRTP may have a positive impact on paranoia and social anxiety, the effects on JTC/belief inflexibility are largely specific to the MRTP. Relationships between social anxiety, JTC, belief inflexibility and paranoia existed in 10/12 individuals, supporting the Threat Anticipation Model

    Supernova Model Discrimination with Hyper-Kamiokande

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    Core-collapse supernovae are among the most magnificent events in the observable universe. They produce many of the chemical elements necessary for life to exist and their remnants—neutron stars and black holes—are interesting astrophysical objects in their own right. However, despite millennia of observations and almost a century of astrophysical study, the explosion mechanism of core-collapse supernovae is not yet well understood. Hyper-Kamiokande is a next-generation neutrino detector that will be able to observe the neutrino flux from the next galactic core-collapse supernova in unprecedented detail. We focus on the first 500 ms of the neutrino burst, corresponding to the accretion phase, and use a newly-developed, high-precision supernova event generator to simulate Hyper-Kamiokande's response to five different supernova models. We show that Hyper-Kamiokande will be able to distinguish between these models with high accuracy for a supernova at a distance of up to 100 kpc. Once the next galactic supernova happens, this ability will be a powerful tool for guiding simulations toward a precise reproduction of the explosion mechanism observed in nature

    Where and How Must JOPP Change to Meet the Challenges of the 21st Century Operating Environment?

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    Jordan Broadworth : Paintings = peintures

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