Adeno-associated virus and lentivirus vectors: a refined toolkit for the central nervous system.

The last two decades have witnessed the increasing instrumentalization of viruses, which have progressively evolved into highly potent gene transfer vehicles for a wide spectrum of applications. In the context of the central nervous system (CNS), their unique gene delivery features and targeting specificities have been exploited not only to improve our understanding of basic neurobiology, but also to investigate diseases or deliver therapeutic candidates. As a result, we have started moving away from the opportunistic use of recombinant vectors that are derived from naturally existing viruses toward the rational engineering of tailored lentivirus (LV) and adeno-associated virus (AAV) vectors for specific use in the CNS

Crystallography, magnetic susceptibility, heat capacity, and electrical resistivity of heavy fermion LiV2_2O4_4 single crystals grown using a self-flux technique

Magnetically pure spinel compound ${\rm LiV_2O_4}$ is a rare $d$-electron heavy fermion. Measurements on single crystals are needed to clarify the mechanism for the heavy fermion behavior in the pure material. In addition, it is known that small concentrations ($< 1$ mol%) of magnetic defects in the structure strongly affect the properties, and measurements on single crystals containing magnetic defects would help to understand the latter behaviors. Herein, we report flux growth of ${\rm LiV_2O_4}$ and preliminary measurements to help resolve these questions. The magnetic susceptibility of some as-grown crystals show a Curie-like upturn at low temperatures, showing the presence of magnetic defects within the spinel structure. The magnetic defects could be removed in some of the crystals by annealing them at 700 $^\circ$C\@. A very high specific heat coefficient $\gamma$ = 450 mJ/(mol K${^2}$\@) was obtained at a temperature of 1.8 K for a crystal containing a magnetic defect concentration $n$${\rm_{defect}}$ = 0.5 mol%. A crystal with $n$${\rm _{defect}}$ = 0.01 mol% showed a residual resistivity ratio of 50.Comment: 6 pages, 7 figures, Title modifie

Designer requirements for visual capability loss simulator tools: Differences between design disciplines

There is a low uptake of inclusive design tools in industry, partly due to a poor fit between design tools and the thought and work processes of designers. Simulating visual capability losses is a technique with great potential in helping designers improve inclusivity and accessibility. However, we need to understand the needs of designers from different disciplines to improve the fit of these tools and their uptake in industry. This study aims to determine designers’ needs for vision loss simulators, and how this varies between disciplines. Interviews were carried out with 15 designers from five disciplines. The results suggest that one tool is not suitable for all. The graphic and web designers interviewed required a tool to aid communication with clients, hoever, the industrial and engineering designers required two tools, depending on the stage of the design process. To increase their uptake, simulator tools should be used in education.We would like to thank the EPSRC for funding this work, and Wolfson College Cambridge for their support.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/978-3-319-07437-5_

Candida albicans Hypha Formation and Mannan Masking of β-Glucan Inhibit Macrophage Phagosome Maturation

Received 28 August 2014 Accepted 28 October 2014 Published 2 December 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license. ACKNOWLEDGMENTS We thank Janet Willment, Aberdeen Fungal Group, University of Aberdeen, for kindly providing the soluble Dectin-1-Fc reporter. All microscopy was performed with the assistance of the University of Aberdeen Core Microscopy & Histology Facility, and we thank the IFCC for their assistance with flow cytometry. We thank the Wellcome Trust for funding (080088, 086827, 075470, 099215, 097377, and 101873). E.R.B. and A.J.P.B. are funded by the European Research Council (ERC-2009-AdG-249793), and J.L. is funded by a Medical Research Council Clinical Training Fellowship.Peer reviewedPublisher PD

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

Aim of this study was the site-specific conjugation of an epidermal growth factor (EGF)-polyethylene glycol (PEG) chain by click chemistry onto a poly(amido amine) (PAMAM) dendron, as a key step toward defined multifunctional carriers for targeted gene delivery. For this purpose, at first propargyl amine cored PAMAM dendrons with ester ends were synthesized. The chain terminal ester groups were then modified by oligoamines with different secondary amino densities. The oligoamine-modified PAMAM dendrons were well biocompatible, as demonstrated in cytotoxicity assays. Among the different oligoamine-modified dendrons, PAMAM-pentaethylenehexamine (PEHA) dendron polyplexes displayed the best gene transfer ability. Conjugation of PAMAM-PEHA dendron with PEG spacer was conducted via click reaction, which was performed before amidation with PEHA. The resultant PEG-PAMAM-PEHA copolymer was then coupled with EGF ligand. pDNA transfections in HuH-7 hepatocellular carcinoma cells showed a 10-fold higher efficiency with the polyplexes containing conjugated EGF as compared to the ligand-free ones, demonstrating the concept of ligand targeting. Overall gene transfer efficiencies, however, were moderate, suggesting that additional measures for overcoming subsequent intracellular bottlenecks in delivery have to be taken

Limits on WWgamma and WWZ Couplings from W Boson Pair Production

The results of a search for W boson pair production in pbar-p collisions at sqrt{s}=1.8 TeV with subsequent decay to emu, ee, and mumu channels are presented. Five candidate events are observed with an expected background of 3.1+-0.4 events for an integrated luminosity of approximately 97 pb^{-1}. Limits on the anomalous couplings are obtained from a maximum likelihood fit of the E_T spectra of the leptons in the candidate events. Assuming identical WWgamma and WWZ couplings, the 95 % C.L. limits are -0.62<Delta_kappa<0.77 (lambda = 0) and -0.53<lambda<0.56 (Delta_kappa = 0) for a form factor scale Lambda = 1.5 TeV.Comment: 10 pages, 1 figure, submitted to Physical Review

Testing variational estimation of process parameters and initial conditions of an earth system model

We present a variational assimilation system around a coarse resolution Earth System Model (ESM) and apply it for estimating initial conditions and parameters of the model. The system is based on derivative information that is efficiently provided by the ESM's adjoint, which has been generated through automatic differentiation of the model's source code. In our variational approach, the length of the feasible assimilation window is limited by the size of the domain in control space over which the approximation by the derivative is valid. This validity domain is reduced by non-smooth process representations. We show that in this respect the ocean component is less critical than the atmospheric component. We demonstrate how the feasible assimilation window can be extended to several weeks by modifying the implementation of specific process representations and by switching off processes such as precipitation

DNA Photocleavage by 9-Aminomethylanthracene Dyes at pH 7.0: Ionic Strength Effects

DNA photosensitizers are compounds that are capable of binding in to DNA strands through groove binding, intercalation, or electrostatic interactions. Excitation of these agents by light generates reactive oxygen species which causes extensive photo-oxidative damage to genomic DNA. Physiological concentrations of NaCl and KCl are ~ 150 mM and 260 mM within the cell nucleus where DNA is contained. Unfortunately, the ability of most photosensitizers to bind to double-helical DNA is reduced and photocleavage yields are diminished as concentrations of salt increase. The aim of this project is to observe the photocleavage of pUC19 plasmid DNA induced by N1,N1-bis(9-anthrymethyl)triethylenetetraamine tetrahydrochloride (AL-VIII 23) 1 or N,N-dimethyl-N’-(9-methylanthracenyl)ethylenediamine (NMEA) 2 in presence of salt. Spectroscopic titrations and DNA melting assays were used to study binding modes and affinities of both dyes to the helix upon the addition of salt

Precise measurement of the top quark mass in the dilepton channel at D0

We measure the top quark mass (mt) in ppbar collisions at a center of mass energy of 1.96 TeV using dilepton ttbar->W+bW-bbar->l+nubl-nubarbbar events, where l denotes an electron, a muon, or a tau that decays leptonically. The data correspond to an integrated luminosity of 5.4 fb-1 collected with the D0 detector at the Fermilab Tevatron Collider. We obtain mt = 174.0 +- 1.8(stat) +- 2.4(syst) GeV, which is in agreement with the current world average mt = 173.3 +- 1.1 GeV. This is currently the most precise measurement of mt in the dilepton channel.Comment: 7 pages, 4 figure