Exogenous schwann cells migrate, remyelinate and promote clinical recovery in experimental auto-immune encephalomyelitis

Schwann cell (SC) transplantation is currently being discussed as a strategy that may promote functional recovery in patients with multiple sclerosis (MS) and other inflammatory demyelinating diseases of the central nervous system (CNS). However this assumes they will not only survive but also remyelinate demyelinated axons in the chronically inflamed CNS. To address this question we investigated the fate of transplanted SCs in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in the Dark Agouti rat; an animal model that reproduces the complex inflammatory demyelinating immunopathology of MS. We now report that SCs expressing green fluorescent protein (GFP-SCs) allografted after disease onset not only survive but also migrate to remyelinate lesions in the inflamed CNS. GFP-SCs were detected more frequently in the parenchyma after direct injection into the spinal cord, than via intra-thecal delivery into the cerebrospinal fluid. In both cases the transplanted cells intermingled with astrocytes in demyelinated lesions, aligned with axons and by twenty one days post transplantation had formed Pzero protein immunoreactive internodes. Strikingly, GFP-SCs transplantation was associated with marked decrease in clinical disease severity in terms of mortality; all GFP-SCs transplanted animals survived whilst 80% of controls died within 40 days of disease

A path unenvisaged to a destination unintended: A collaborative autoethnographic account of becoming a community of practice in an HEI

In this paper we explore how a disparate group of predominately foundation phase teacher educators unintentionally, over a period of time, came together to form a strong community of practice (CoP). Voluntary involvement in a research project positioned this group of lecturers in unaccustomed roles and necessitated that they engage with each other in a variety of ways to meet project outcomes. New relationships developed as people took on different roles and new responsibilities emerged as the group faced challenges. As this was a subjective interrogation of our experiences, a research method such as autoethnography where we could focus on the experience and processes of becoming a CoP, rather than the outcomes of the research itself, seemed appropriate. We outline our understandings of a CoP and show how, through a critical self-reflective process, we were able to strengthen both our teaching and research practices in a Higher Education Institution (HEI). The strengthening occurred, in part, due to the formation and development of this CoP

Production and characterization of monoclonal antibodies to the extracellular domain of PO

Seven monoclonal antibodies were raised against the immunoglobulin-like extracellular domain of PO (POED), the major protein of peripheral nervous system myelin. Mice were immunized with purified recombinant rat PO-ED. After fusion, 7 clones (POI-P07) recognizing either recombinant, rat, mouse, or human PO-ED were selected by ELlS A and were characterized by Western blot, immunohistochemistry, and a competition assay. Antibodies belonged to the IgG or IgM class, and P04-P07, reacted with PO in fresh-frozen and paraffin-embedded sections of human or rat peripheral nerve, but not with myelin proteins of the central nervous system of either species. Epitope specificity of the antibodies was determined by a competition enzyme-linked immunosorbent assay (ELISA) and a direct ELlS A using short synthetic peptides spanning the entire extracellular domain of PO. These assays showed that POl and P02 exhibiting the same reaction pattern in Western blot and immunohistochemistry reacted with different distant epitopes of PO. Furthermore, the monoclonal antibodies P05 and P06 recognized 2 different epitopes in close proximity within the neuritogenic extracellular sequence of PO. This panel of monoclonal antibodies, each binding to a different epitope of the extracellular domain of PO, will be useful for in vitro and in vivo studies designed to explore the role of PO during myelination and in demyelinating diseases of the peripheral nervous system

Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected

The recent global outbreak of Zika virus (ZIKV) infection has been linked to severe neurological disorders affecting the peripheral and central nervous systems (PNS and CNS, respectively). The pathobiology underlying these diverse clinical phenotypes are the subject of intense research; however, even the principal neural cell types vulnerable to productive Zika infection remain poorly characterised. Here we used CNS and PNS myelinating cultures from wild type and Ifnar1 knockout mice to examine neuronal and glial tropism and short-term consequences of direct infection with a Brazilian variant of ZIKV. Cell cultures were infected pre- or post-myelination for various intervals, then stained with cell-type and ZIKV-specific antibodies. In bypassing systemic immunity using ex vivo culture, and the type I interferon response in Ifnar1 deficient cells, we were able to evaluate the intrinsic infectivity of neural cells. Through systematic quantification of ZIKV infected cells in myelinating cultures, we found that ZIKV infection is enhanced in the absence of the type I interferon responses and that CNS cells are considerably more susceptible to infection than PNS cells. In particular, we demonstrate that CNS axons and myelinating oligodendrocytes are especially vulnerable to injury. These results have implications for understanding the pathobiology of neurological symptoms associated with ZIKV infection. Furthermore, we provide a quantifiable ex vivo infection model that can be used for fundamental and therapeutic studies on viral neuroinvasion and its consequences

On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds.

Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat

Review: ‘Gimme five’: future challenges in multiple sclerosis. ECTRIMS Lecture 2009

This article is based on the ECTRIMS lecture given at the 25th ECTRIMS meeting which was held in Düsseldorf, Germany, from 9 to 12 September 2009. Five challenges have been identified: (1) safeguarding the principles of medical ethics; (2) optimizing the risk/benefit ratio; (3) bridging the gap between multiple sclerosis and experimental autoimmune encephalitis; (4) promoting neuroprotection and repair; and (5) tailoring multiple sclerosis therapy to the individual patient. Each of these challenges will be discussed and placed in the context of current research into the pathogenesis and treatment of multiple sclerosis

Maternal neurofascin-specific autoantibodies bind to structures of the fetal nervous system during pregnancy, but have no long term effect on development in the rat

Neurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum. Results: Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody. Conclusions: We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children

Robust control of quantized motional states of a chain of trapped ions by collective adiabatic passage

A simple technique for robust generation of vibrational Fock states in a chain of trapped ions is proposed. The method is fast and easy to implement, since only a single chirped laser pulse, simultaneously addressing all of the ions, is required. Furthermore, because the approach uses collective adiabatic passage, significant fluctuations in the intensity or frequency of the laser pulse can be tolerated, and the technique performs well even on the border of the Lamb-Dicke regime. We also demonstrate how this technique may be extended in order to create non-classical superposition states of the ions' collective motion and Greenberger-Horne-Zeilinger states of their internal states. Because only a single laser pulse is required, heating effects arising under realistic experimental conditions are negligibly small.Comment: 9 pages, 7 figures. Discussion of performance outside Lamb-Dicke regime added. Some refs adde

Additivity and non-additivity of multipartite entanglement measures

We study the additivity property of three multipartite entanglement measures, i.e. the geometric measure of entanglement (GM), the relative entropy of entanglement and the logarithmic global robustness. First, we show the additivity of GM of multipartite states with real and non-negative entries in the computational basis. Many states of experimental and theoretical interests have this property, e.g. Bell diagonal states, maximally correlated generalized Bell diagonal states, generalized Dicke states, the Smolin state, and the generalization of D\"{u}r's multipartite bound entangled states. We also prove the additivity of other two measures for some of these examples. Second, we show the non-additivity of GM of all antisymmetric states of three or more parties, and provide a unified explanation of the non-additivity of the three measures of the antisymmetric projector states. In particular, we derive analytical formulae of the three measures of one copy and two copies of the antisymmetric projector states respectively. Third, we show, with a statistical approach, that almost all multipartite pure states with sufficiently large number of parties are nearly maximally entangled with respect to GM and relative entropy of entanglement. However, their GM is not strong additive; what's more surprising, for generic pure states with real entries in the computational basis, GM of one copy and two copies, respectively, are almost equal. Hence, more states may be suitable for universal quantum computation, if measurements can be performed on two copies of the resource states. We also show that almost all multipartite pure states cannot be produced reversibly with the combination multipartite GHZ states under asymptotic LOCC, unless relative entropy of entanglement is non-additive for generic multipartite pure states.Comment: 45 pages, 4 figures. Proposition 23 and Theorem 24 are revised by correcting a minor error from Eq. (A.2), (A.3) and (A.4) in the published version. The abstract, introduction, and summary are also revised. All other conclusions are unchange

Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9

The failure of remyelination in multiple sclerosis is largely unexplained. Lindner et al. report that glial cells in demyelinating lesions show increased expression of fibroblast growth factor 9 (FGF9). This induces astrocyte-dependent responses that inhibit remyelination and stimulate expression of pro-inflammatory chemokines, supporting a feedback loop that amplifies disease activit