Heterodimeric glycolipid complexes as targets for neuropathy associated pathogenic autoantibodies and other lectins

There is plentiful evidence that the pathology of Guillain Barré syndrome (GBS) is driven by autoantibodies generated following infection. A number of inconsistencies with this theory remain, and in many clinical cases such antibodies are not detected. Recent descriptions of ganglioside complex (GSC) antibodies suggest a potential explanation for this. This study aimed to further investigate GSCs and associated antibodies with a particular focus on GBS. GSCs were found to modulate the binding of other lectins such as bacterial toxins, immunomodulatory receptors, and monoclonal antibodies. The development of a semi-automated array system allowed screening of a large cohort of GBS sera against multiple complexes, revealing a greater antibody detection rate (particularly in demyelinating forms) than had previously been achieved. Binding that was both enhanced and attenuated by complexes was seen, and this varied between disease and control sera. Immunisation experiments provided insights into the generation of the GSC immune response. A transgenic mouse model of GBS was also developed, demonstrating that local axonal expression of gangliosides does not induce systemic tolerance. The work described in this thesis has thus significantly advanced knowledge in the field of glycolipid complexes, particularly with respect to anti-glycolipid complex antibodies and their association with inflammatory neuropathies such as Guillain-Barré syndrome

Nodes, paranodes and neuropathies

This review summarises recent evidence supporting the involvement of the specialised nodal and perinodal domains (the paranode and juxtaparanode) of myelinated axons in the pathology of acquired, inflammatory, peripheral neuropathies.The identification of new target antigens in the inflammatory neuropathies heralds a revolution in diagnosis, and has already begun to inform increasingly targeted and individualised therapies. Rapid progress in our basic understanding of the highly specialised nodal regions of peripheral nerves serves to strengthen the links between their unique microstructural identities, functions and pathologies. In this context, the detection of autoantibodies directed against nodal and perinodal targets is likely to be of increasing clinical importance. Antiganglioside antibodies have long been used in clinical practice as diagnostic serum biomarkers, and associate with specific clinical variants but not to the common forms of either acute or chronic demyelinating autoimmune neuropathy. It is now apparent that antibodies directed against several region-specific cell adhesion molecules, including neurofascin, contactin and contactin-associated protein, can be linked to phenotypically distinct peripheral neuropathies. Importantly, the immunological characteristics of these antibodies facilitate the prediction of treatment responsiveness

Guillain‐Barré syndrome: A comprehensive review

Guillain‐Barré syndrome (GBS) is a potentially devastating yet treatable disorder. A classically postinfectious, immune‐mediated, monophasic polyradiculoneuropathy, it is the leading global cause of acquired neuromuscular paralysis. In most cases, the immunopathological process driving nerve injury is ill‐defined. Diagnosis of GBS relies on clinical features, supported by laboratory findings and electrophysiology. Although previously divided into primary demyelinating or axonal variants, this dichotomy is increasingly challenged, and is not endorsed by the recent European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) guidelines. Intravenous immunoglobulin and plasma exchange remain the primary modalities of treatment, regardless of the electrophysiological subtype. Most patients recover, but approximately one‐third require mechanical ventilation, and 5% die. Disease activity and treatment response are currently monitored through interval neurological examination and outcome measures, and the potential role of fluid biomarkers is under ongoing scrutiny. Novel potential therapies for GBS are being explored but none have yet modified clinical practice. This review provides a comprehensive update on the pathological and clinical aspects of GBS for clinicians and scientists

Detection of interaction articles and experimental methods in biomedical literature

Background: This article describes the approaches taken by the OntoGene group at the University of Zurich in dealing with two tasks of the BioCreative III competition: classification of articles which contain curatable protein- protein interactions (PPI-ACT) and extraction of experimental methods (PPI-IMT). Results: Two main achievements are described in this paper: (a) a system for document classification which crucially relies on the results of an advanced pipeline of natural language processing tools; (b) a system which is capable of detecting all experimental methods mentioned in scientific literature, and listing them with a competitive ranking (AUC iP/R > 0.5). Conclusions: The results of the BioCreative III shared evaluation clearly demonstrate that significant progress has been achieved in the domain of biomedical text mining in the past few years. Our own contribution, together with the results of other participants, provides evidence that natural language processing techniques have become by now an integral part of advanced text mining approaches

On the stability of scale-invariant black holes

Quadratic scale-invariant gravity non minimally coupled to a scalar field provides a competitive model for inflation, characterized by the transition from an unstable to a stable fixed point, both characterized by constant scalar field configurations. We provide a complementary analysis of the same model in the static, spherically symmetric setting, obtaining two Schwarzschild-de Sitter solutions, which corresponds to the two fixed points existing in the cosmological scenario. The stability of such solutions is thoroughly investigated from two different perspectives. First, we study the system at the classical level by the analysis of linear perturbations. In particular, we provide both analytical and numerical results for the late-time behavior of the perturbations, proving the stable and unstable character of the two solutions. Then we perform a semi-classical, non-linear analysis based on the Euclidean path integral formulation. By studying the difference between the Euclidean on-shell actions evaluated on both solutions, we prove that the unstable one has a meta-stable character and is spontaneously decaying into the stable fixed point which is always favoured.Comment: 21 pages, 5 figure

Ultrasensitive assay technology and fluid biomarkers for the evaluation of peripheral nerve disease

The field of biomarker discovery is rapidly expanding. The introduction of ultrasensitive immunoassays and the growing precision of genetic technologies are poised to revolutionise the assessment and monitoring of many diseases. Given the difficulties in imaging and tissue diagnosis, there is mounting interest in serum and cerebrospinal fluid biomarkers of peripheral neuropathy. Realised and potential fluid biomarkers of peripheral nerve disease include neuronal biomarkers of axonal degeneration, glial biomarkers for peripheral demyelinating disorders, immunopathogenic biomarkers (such as the presence and titre of antibodies or the levels of cytokines) and genetic biomarkers. Several are already starting to inform clinical practice, whereas others remain under evaluation as potential indicators of disease activity and treatment response. As more biomarkers become available for clinical use, it has become increasingly difficult for clinicians and researchers to keep up-to-date with the most recent discovery and interpretation. In this review, we aim to inform practising neurologists, neuroscientists and other clinicians about recent advances in fluid biomarker technology, with a focus on single molecule arrays (Simoa), chemiluminescent enzyme immunoassays (CLEIA), electrochemiluminescence (ECL), proximity extension assays (PEA), and microfluidic technology. We discuss established and emerging fluid biomarkers of peripheral neuropathy, their clinical applications, limitations and potential future developments