Antibody mediated neutralization of myelin associated EphrinB3 accelerates CNS remyelination

This is the final version of the article. It was first available from Springer via http://dx.doi.org/10.1007/s00401-015-1521-1Remyelination in multiple sclerosis (MS) lesions often remains incomplete despite the presence of oligodendrocyte progenitor cells (OPCs). Amongst other factors, successful remyelination depends on the phagocytic clearance of myelin debris. However, the proteins in myelin debris that act as potent and selective inhibitors on OPC differentiation and inhibit CNS remyelination remain unknown. Here, we identify the transmembrane signalling protein EphrinB3 as important mediator of this inhibition, using a protein analytical approach in combination with a primary rodent OPC assay. In the presence of EphrinB3, OPCs fail to differentiate. In a rat model of remyelination, infusion of EphrinB3 inhibits remyelination. In contrast, masking EphrinB3 epitopes using antibodies promotes remyelination. Finally, we identify EphrinB3 in MS lesions and demonstrate that MS lesion extracts inhibit OPC differentiation while antibody-mediated masking of EphrinB3 epitopes promotes it. Our findings suggest that EphrinB3 could be a target for therapies aiming at promoting remyelination in demyelinating disease.This work was supported by the UK MS Society Grant ref: 941/11. MRNK held a NIHR Clinical Lectureship. KAN was supported by an ERC advanced award

Antimicrobial efficacy of low concentration PVP-silver nanoparticles deposited on DBD plasma-treated polyamide 6,6 fabric

In this study, a low concentration (10 μg·mL−1) of poly(N-vinylpyrrolidone) (PVP)-coated silver nanoparticles (AgNPs) were deposited by spray and exhaustion (30, 70 and 100 ◦C) methods onto untreated and dielectric barrier discharge (DBD) plasma-treated polyamide 6,6 (PA66) fabric. DBD plasma-treated samples showed higher AgNP deposition than untreated ones for all methods. After five washing cycles, only DBD plasma-treated samples displayed AgNPs on the fabric surface. The best-performing method was exhaustion at 30 ◦C, which exhibited less agglomeration and the best antibacterial efficacy against S. aureus (4 log reduction). For E. coli, the antimicrobial effect showed good results in all the exhaustion samples (5 log reduction). Considering the spray method, only the DBD plasma-treated samples showed some bacteriostatic activity for both strains, but the AgNP concentration was not enough to have a bactericidal effect. Our results suggest DBD plasma may be a low cost and chemical-free method for the preparation of antibacterial textiles, allowing for the immobilization of a very low—but effective—concentration of AgNPs.This work was funded by European Regional Development funds (FEDER) through the Competitiveness and Internationalization Operational Program (POCI) – COMPETE and by National Funds through Fundação para a Ciência e Tecnologia (FCT)—under the project POCI-01-0145-FEDER-007136 and UID/CTM/00264/2019. Isabel Ribeiro (SFRH/BD/137668/2018) acknowledges FCT, Portugal, for its doctoral grant financial support. A. Zille also acknowledges financial support of the FCT through an Investigator FCT Research contract (IF/00071/2015) and the project PTDC/CTM-TEX/28295/2017 financed by FCT, FEDER and POCI in the frame of the Portugal 2020 program

Design of a Gd-DOTA-Phthalocyanine Conjugate Combining MRI Contrast Imaging and Photosensitization Properties as a Potential Molecular Theranostic

Cataloged from PDF version of article.The design and synthesis of a phthalocyanine - Gd-DOTA conjugate is presented to open the way to novel molecular theranostics, combining the properties of MRI contrast imaging with photodynamic therapy. The rational design of the conjugate integrates isomeric purity of the phthalocyanine core substitution, suitable biocompatibility with the use of polyoxo water-solubilizing substituents, and a convergent synthetic strategy ended by the use of click chemistry to graft the Gd-DOTA moiety to the phthalocyanine. Photophysical and photochemical properties, contrast imaging experiments and preliminary in vitro investigations proved that such a combination is relevant and lead to a new type of potential theranostic agent

EMAS position statement : Predictors of premature and early natural menopause

Introduction: While the associations of genetic, reproductive and environmental factors with the timing of natural menopause have been extensively investigated, few epidemiological studies have specifically examined their association with premature (<40 years) or early natural menopause (40-45 years). Aim: The aim of this position statement is to provide evidence on the predictors of premature and early natural menopause, as well as recommendations for the management of premature and early menopause and future research. Materials and methods: Literature review and consensus of expert opinion. Results and conclusions: Strong genetic predictors of premature and early menopause include a family history of premature or early menopause, being a child of a multiple pregnancy and some specific genetic variants. Women with early menarche and nulliparity or low parity are also at a higher risk of experiencing premature or early menopause. Cigarette smoking (with a strong dose-response effect) and being underweight have been consistently associated with premature and early menopause. Current guidelines for the management of premature and early menopause mainly focus on early initiation of hormone therapy (HT) and continued treatment until the woman reaches the average age at menopause (50-52 years). We suggest that clinicians and health professionals consider the age at menopause of the relevant region or ethnic group as part of the assessment for the timing of HT cessation. In addition, there should be early monitoring of women with a family history of early menopause, who are a child of a multiple pregnancy, or who have had early menarche (especially those who have had no children). As part of preventive health strategies, women should be encouraged to quit smoking (preferably before the age of 30 years) and maintain optimal weight in order to reduce their risk of premature or early menopause.Peer reviewe

Rapid and tunable method to temporally control gene editing based on conditional Cas9 stabilization

The CRISPR/Cas9 system is a powerful tool for studying gene function. Here, we describe a method that allows temporal control of CRISPR/Cas9 activity based on conditional Cas9 destabilization. We demonstrate that fusing an FKBP12-derived destabilizing domain to Cas9 (DD-Cas9) enables conditional Cas9 expression and temporal control of gene editing in the presence of an FKBP12 synthetic ligand. This system can be easily adapted to co-express, from the same promoter, DD-Cas9 with any other gene of interest without co-modulation of the latter. In particular, when co-expressed with inducible Cre-ERT2, our system enables parallel, independent manipulation of alleles targeted by Cas9 and traditional recombinase with single-cell specificity. We anticipate this platform will be used for the systematic characterization and identification of essential genes, as well as the investigation of the interactions between functional genes

VERITAS Search for VHE Gamma-ray Emission from Dwarf Spheroidal Galaxies

Indirect dark matter searches with ground-based gamma-ray observatories provide an alternative for identifying the particle nature of dark matter that is complementary to that of direct search or accelerator production experiments. We present the results of observations of the dwarf spheroidal galaxies Draco, Ursa Minor, Bootes 1, and Willman 1 conducted by VERITAS. These galaxies are nearby dark matter dominated objects located at a typical distance of several tens of kiloparsecs for which there are good measurements of the dark matter density profile from stellar velocity measurements. Since the conventional astrophysical background of very high energy gamma rays from these objects appears to be negligible, they are good targets to search for the secondary gamma-ray photons produced by interacting or decaying dark matter particles. No significant gamma-ray flux above 200 GeV was detected from these four dwarf galaxies for a typical exposure of ~20 hours. The 95% confidence upper limits on the integral gamma-ray flux are in the range 0.4-2.2x10^-12 photons cm^-2s^-1. We interpret this limiting flux in the context of pair annihilation of weakly interacting massive particles and derive constraints on the thermally averaged product of the total self-annihilation cross section and the relative velocity of the WIMPs. The limits are obtained under conservative assumptions regarding the dark matter distribution in dwarf galaxies and are approximately three orders of magnitude above the generic theoretical prediction for WIMPs in the minimal supersymmetric standard model framework. However significant uncertainty exists in the dark matter distribution as well as the neutralino cross sections which under favorable assumptions could further lower the limits.Comment: 21 pages, 2 figures, updated to reflect version published in ApJ. NOTE: M.D. Wood added as autho

Discovery of very high energy gamma rays from PKS 1424+240 and multiwavelength constraints on its redshift

We report the first detection of very-high-energy (VHE) gamma-ray emission above 140 GeV from PKS 1424+240, a BL Lac object with an unknown redshift. The photon spectrum above 140 GeV measured by VERITAS is well described by a power law with a photon index of 3.8 +- 0.5_stat +- 0.3_syst and a flux normalization at 200 GeV of (5.1 +- 0.9_stat +- 0.5_syst) x 10^{-11} TeV^-1 cm^-2 s^-1, where stat and syst denote the statistical and systematical uncertainty, respectively. The VHE flux is steady over the observation period between MJD 54881 and 55003 (2009 February 19 to June 21). Flux variability is also not observed in contemporaneous high energy observations with the Fermi Large Area Telescope (LAT). Contemporaneous X-ray and optical data were also obtained from the Swift XRT and MDM observatory, respectively. The broadband spectral energy distribution (SED) is well described by a one-zone synchrotron self-Compton (SSC) model favoring a redshift of less than 0.1. Using the photon index measured with Fermi in combination with recent extragalactic background light (EBL) absorption models it can be concluded from the VERITAS data that the redshift of PKS 1424+240 is less than 0.66.Comment: accepted for publication, Ap

Abnormal ECG Findings in Athletes: Clinical Evaluation and Considerations.

PURPOSE OF REVIEW: Pre-participation cardiovascular evaluation with electrocardiography is normal practice for most sporting bodies. Awareness about sudden cardiac death in athletes and recognizing how screening can help identify vulnerable athletes have empowered different sporting disciplines to invest in the wellbeing of their athletes. RECENT FINDINGS: Discerning physiological electrical alterations due to athletic training from those representing cardiac pathology may be challenging. The mode of investigation of affected athletes is dependent on the electrical anomaly and the disease(s) in question. This review will highlight specific pathological ECG patterns that warrant assessment and surveillance, together with an in-depth review of the recommended algorithm for evaluation