Glycine receptor autoantibodies disrupt inhibitory neurotransmission

Chloride-permeable glycine receptors have an important role in fast inhibitory neurotransmission in the spinal cord and brainstem. Human immunoglobulin G (IgG) autoantibodies to glycine receptors are found in a substantial proportion of patients with progressive encephalomyelitis with rigidity and myoclonus, and less frequently in other variants of stiff person syndrome. Demonstrating a pathogenic role of glycine receptor autoantibodies would help justify the use of immunomodulatory therapies and provide insight into the mechanisms involved. Here purified IgGs from four patients with progressive encephalomyelitis with rigidity and myoclonus or stiff person syndrome and glycine receptor autoantibodies were observed to profoundly disrupt glycinergic neurotransmission. In whole cell patch clamp recordings from cultured rat spinal motoneurons, glycinergic synaptic currents were almost completely abolished following incubation in patient IgGs. Most human autoantibodies targeting other CNS neurotransmitter receptors, such as N-methyl-D-aspartate (NMDA) receptors, affect whole cell currents only after several hours’ incubation and this effect has been shown to be the result of antibody-mediated crosslinking and internalisation of receptors. By contrast, we observed substantial reductions in glycinergic currents with all four patient IgG preparations with 15 minutes of exposure to patient IgGs. Moreover, monovalent Fab fragments generated from the purified IgG of three of the four patients also profoundly reduced glycinergic currents compared with control Fab-IgG. We conclude that human glycine receptor autoantibodies disrupt glycinergic neurotransmission, and also suggest that the pathogenic mechanisms include direct antagonistic actions on glycine receptors.SJC is supported by from the Wellcome Trust (101696/Z/13/Z), the National Institute for Health Research (NIHR), BMA Foundation for Medical Research (Vera Down Award 2017) and the National Organisation for Rare Disorders (16006). CLD is supported by the Wellcome Trust. SRI is supported by the Wellcome Trust (104079/Z/14/Z), BMA Research Grants- Vera Down grant (2013) and Margaret Temple (2017), and by Epilepsy Research UK (P1201). The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC; The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health). LJ, MIL and AV received support from the Nuffield Department of Clinical Neurosciences. DMK is supported by the Wellcome Trust, Medical Research Council and Epilepsy Research UK

Rethinking the impact of regeneration on poverty: a (partial) defence of a 'failed' policy

For decades regeneration programmes in England targeted areas where spatial concentrations of poverty exist. These 'area-based initiatives' (ABIs) came under sustained attack, however, from the previous coalition government for being expensive and ineffective. This paper assesses this claim by re-evaluating past evidence on the impact of regeneration on poverty. It finds regeneration did relatively little to transform households' material circumstances but significantly ameliorated negative experiences of living in poverty in relation to housing, community safety and the physical environment. This partially undermines the rationale for the policy shift away from neighbourhood renewal interventions toward the current focus on 'local growth' as the sole remedy for spatial inequalities. It also suggests a need for more nuance in wider critical accounts of regeneration as a deepening form of neoliberalism

Ethnic minority customers of the Pensions, Disability and Carers Service: an evidence review.

The aim of this project was to review and synthesise available evidence that could throw light on: why Black and Minority Ethnic (BME) customers are less satisfied with the Pension, Disability and Carers Service (PDCS); why BME individuals eligible for the PDCS benefits are less likely to apply for them; what interventions might be successful at raising levels of take-up and satisfaction with PDCS services; and what important gaps exist in research evidence to answer these questions

Antibody-mediated central nervous system diseases.

Antibody-mediated central nervous system diseases are a relatively new area of clinical neuroscience with growing impact. Their recognition has challenged the dogma of the blood-brain barrier preventing antibody access into the central nervous system. The antibodies discovered so far are mainly against neurotransmitter receptors (e.g. N-methyl-d-aspartate and glycine receptors) and ion channel-associated proteins (leucine-rich glioma inactivated protein 1 and contactin-associated protein 2) and are expressed on the surface of neuronal synapses and elsewhere. The disorders are reversible with immunotherapies that reduce antibody levels. Although rare, the identification of these disorders in clinical practice has made central nervous system autoimmune diseases a consideration in the differential diagnoses of many clinical presentations. There is still much to learn about the aetiology of the diseases and the mechanisms by which the antibodies act, the neuronal and glial changes that follow antibody-attack, and the compensatory changes that may be required to ensure good recovery

Envisioning An Equitable Central City

This Master of Urban and Regional Planning (MURP) Workshop project working with our clients, City of Portland’s Bureau of Transportation and Bureau of Planning and Sustainability, advances the pursuit of equity within Portland’s Central City. Six MURP students acted as the consultant, under the name VF Planning, and with the guidance of Portland State University professors. Portland’s Central City (CC) stretches from the West Hills to SE 12th Avenue and includes ten subdistricts: Lower Albina, Lloyd, and Central Eastside to the east and Pearl, Old Town/Chinatown, Goose Hollow, West End, Downtown, South Downtown/University, and South Waterfront to the west of the Willamette River. The CC is the foundation of Portland’s affordable, equitable, and sustainable future. It has the city’s highest concentration of affordable housing, residential diversity, jobs, cultural amenities, and higher education opportunities. The CC also serves as a transportation and economic hub for the city and the region. It acts as a small business incubator, and is the civic heart of our city. The CC is a tapestry of rich cultural history and resilience as well as pain and displacement. It represents only 3% of Portland’s land area but holds 11% of our city’s housing units and is intended to accommodate 30% of the city’s projected growth. Through analysis of existing conditions and stakeholder outreach, the consultant used an equity lens to identify stakeholder interests and needs in the CC. With promising practices in mind, VF Planning developed recommendations to progress toward the vision of an equitable and thriving CC. This work will serve as a new touchstone for Portland’s Bureau of Transportation (PBOT) and Bureau of Planning & Sustainability (BPS) to use as they prioritize equity in the CC

Proto‐Urea‐RNA (Wöhler RNA) Containing Unusually Stable Urea Nucleosides

The RNA world hypothesis assumes that life on Earth began with nucleotides that formed information‐carrying RNA oligomers able to self‐replicate. Prebiotic reactions leading to the contemporary nucleosides are now known, but their execution often requires specific starting materials and lengthy reaction sequences. It was therefore proposed that the RNA world was likely proceeded by a proto‐RNA world constructed from molecules that were likely present on the early Earth in greater abundance. Herein, we show that the prebiotic starting molecules bis‐urea (biuret) and tris‐urea (triuret) are able to directly react with ribose. The urea‐ribosides are remarkably stable because they are held together by a network of intramolecular, bifurcated hydrogen bonds. This even allowed the synthesis of phosphoramidite building blocks and incorporation of the units into RNA. Investigations of the nucleotides’ base‐pairing potential showed that triuret:G RNA base pairs closely resemble U:G wobble base pairs. Based on the probable abundance of urea on the early Earth, we postulate that urea‐containing RNA bases are good candidates for a proto‐RNA world