Longitudinal intravital imaging of the retina reveals long-term dynamics of immune infiltration and its effects on the glial network in experimental autoimmune uveoretinitis, without evident signs of neuronal dysfunction in the ganglion cell layer

A hallmark of autoimmune retinal inflammation is the infiltration of the retina with cells of the innate and adaptive immune system, leading to detachment of the retinal layers and even to complete loss of the retinal photoreceptor layer. As the only optical system in the organism, the eye enables non-invasive longitudinal imaging studies of these local autoimmune processes and of their effects on the target tissue. Moreover, as a window to the central nervous system (CNS), the eye also reflects general neuroinflammatory processes taking place at various sites within the CNS. Histological studies in murine neuroinflammatory models, such as experimental autoimmune uveoretinitis (EAU) and experimental autoimmune encephalomyelitis, indicate that immune infiltration is initialized by effector CD4(+) T cells, with the innate compartment (neutrophils, macrophages, and monocytes) contributing crucially to tissue degeneration that occurs at later phases of the disease. However, how the immune attack is orchestrated by various immune cell subsets in the retina and how the latter interact with the target tissue under in vivo conditions is still poorly understood. Our study addresses this gap with a novel approach for intravital two-photon microscopy, which enabled us to repeatedly track CD4(+) T cells and LysM phagocytes during the entire course of EAU and to identify a specific radial infiltration pattern of these cells within the inflamed retina, starting from the optic nerve head. In contrast, highly motile [Formula: see text] cells display an opposite radial motility pattern, toward the optic nerve head. These inflammatory processes induce modifications of the microglial network toward an activated morphology, especially around the optic nerve head and main retinal blood vessels, but do not affect the neurons within the ganglion cell layer. Thanks to the new technology, non-invasive correlation of clinical scores of CNS-related pathologies with immune infiltrate behavior and subsequent tissue dysfunction is now possible. Hence, the new approach paves the way for deeper insights into the pathology of neuroinflammatory processes on a cellular basis, over the entire disease course

Serum peptide reactivities may distinguish neuromyelitis optica subgroups and multiple sclerosis

Objective: To assess in an observational study whether serum peptide antibody reactivities may distinguish aquaporin-4 (AQP4) antibody (Ab)–positive and -negative neuromyelitis optica spectrum disorders (NMOSD) and relapsing-remitting multiple sclerosis (RRMS). Methods: We screened 8,700 peptides that included human and viral antigens of potential relevance for inflammatory demyelinating diseases and random peptides with pooled sera from different patient groups and healthy controls to set up a customized microarray with 700 peptides. With this microarray, we tested sera from 66 patients with AQP4-Ab-positive (n = 16) and AQP4-Ab-negative (n = 19) NMOSD, RRMS (n = 11), and healthy controls (n = 20). Results: Differential peptide reactivities distinguished NMOSD subgroups from RRMS in 80% of patients. However, the 2 NMOSD subgroups were not well-discriminated, although those patients are clearly separated by their antibody reactivities against AQP4 in cell-based assays. Elevated reactivities to myelin and Epstein-Barr virus peptides were present in RRMS and to AQP4 and AQP1 peptides in AQP4-Ab-positive NMOSD. Conclusions: While AQP4-Ab-positive and -negative NMOSD subgroups are not well-discriminated by peptide antibody reactivities, our findings suggest that peptide antibody reactivities may have the potential to distinguish between both NMOSD subgroups and MS. Future studies should thus concentrate on evaluating peptide antibody reactivities for the differentiation of AQP4-Ab-negative NMOSD and MS

On the Second Law of thermodynamics and the piston problem

The piston problem is investigated in the case where the length of the cylinder is infinite (on both sides) and the ratio $m/M$ is a very small parameter, where $m$ is the mass of one particle of the gaz and $M$ is the mass of the piston. Introducing initial conditions such that the stochastic motion of the piston remains in the average at the origin (no drift), it is shown that the time evolution of the fluids, analytically derived from Liouville equation, agrees with the Second Law of thermodynamics. We thus have a non equilibrium microscopical model whose evolution can be explicitly shown to obey the two laws of thermodynamics.Comment: 29 pages, 9 figures submitted to Journal of Statistical Physics (2003

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin

BACKGROUND: Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. OBJECTIVE: To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. METHODS: 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. RESULTS: MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7 %) patients with a history of both ON and myelitis, 22/103 (21.4 %) with a history of ON but no myelitis and 6/45 (13.3 %) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67 %) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89 %) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. CONCLUSIONS: To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status

AlignNemo: A Local Network Alignment Method to Integrate Homology and Topology

Local network alignment is an important component of the analysis of protein-protein interaction networks that may lead to the identification of evolutionary related complexes. We present AlignNemo, a new algorithm that, given the networks of two organisms, uncovers subnetworks of proteins that relate in biological function and topology of interactions. The discovered conserved subnetworks have a general topology and need not to correspond to specific interaction patterns, so that they more closely fit the models of functional complexes proposed in the literature. The algorithm is able to handle sparse interaction data with an expansion process that at each step explores the local topology of the networks beyond the proteins directly interacting with the current solution. To assess the performance of AlignNemo, we ran a series of benchmarks using statistical measures as well as biological knowledge. Based on reference datasets of protein complexes, AlignNemo shows better performance than other methods in terms of both precision and recall. We show our solutions to be biologically sound using the concept of semantic similarity applied to Gene Ontology vocabularies. The binaries of AlignNemo and supplementary details about the algorithms and the experiments are available at: sourceforge.net/p/alignnemo

A Novel Framework for the Comparative Analysis of Biological Networks

Genome sequencing projects provide nearly complete lists of the individual components present in an organism, but reveal little about how they work together. Follow-up initiatives have deciphered thousands of dynamic and context-dependent interrelationships between gene products that need to be analyzed with novel bioinformatics approaches able to capture their complex emerging properties. Here, we present a novel framework for the alignment and comparative analysis of biological networks of arbitrary topology. Our strategy includes the prediction of likely conserved interactions, based on evolutionary distances, to counter the high number of missing interactions in the current interactome networks, and a fast assessment of the statistical significance of individual alignment solutions, which vastly increases its performance with respect to existing tools. Finally, we illustrate the biological significance of the results through the identification of novel complex components and potential cases of cross-talk between pathways and alternative signaling routes

Endothelin 1 levels in relation to clinical presentation and outcome of Henoch Schonlein purpura

<p>Abstract</p> <p>Background</p> <p>Henoch Schonlein purpura (HSP) is a common vasculitis of small vessels whereas endothelin-1 (ET-1) is usually reported elevated in vasculities and systematic inflammation. The aim of the present study was to investigate whether ET-1 levels are correlated with the clinical presentation and the outcome of HSP.</p> <p>Methods</p> <p>The study sample consisted of thirty consecutive patients with HSP. An equal number of healthy patients of similar age and the same gender were served as controls. The patients' age range was 2–12.6 years with a mean ± SD = 6.3 ± 3 years. All patients had a physical examination with a renal, and an overall clinical score. Blood and urinary biochemistry, immunology investigation, a skin biopsy and ET-1 measurements in blood and urine samples were made at presentation, 1 month later and 1 year after the appearance of HSP. The controls underwent the same investigation with the exception of skin biopsy.</p> <p>Results</p> <p>ET-1 levels in plasma and urine did not differ between patients and controls at three distinct time points. Furthermore the ET-1 were not correlated with the clinical score and renal involvement was independent from the ET-1 measurements. However, the urinary ET-1 levels were a significant predictor of the duration of the acute phase of HSP (HR = 0.98, p = 0.032, CI0.96–0.99). The ET-1 levels did not correlate with the duration of renal involvement.</p> <p>Conclusion</p> <p>Urinary ET-1 levels are a useful marker for the duration of the acute phase of HSP but not for the length of renal involvement.</p

Sailing into a dilemma : an economic and legal analysis of an EU trading scheme for maritime emissions

On the basis of a joint economic and legal analysis, we evaluate the effects of a “regional” (European) emission trading scheme aiming at reducing emissions of international shipping. The focus lies on the question which share of emissions from maritime transport activities to and from the EU can and should be included in such a system. Our findings suggest that the attempt to implement an EU maritime ETS runs into a dilemma. It is not possible to design a system that achieves emission reductions in a cost efficient manner and is compatible with international law

An Integrated Framework for Intersectorality: Nonprofitness and Its Influence on Society and Public Administration Programs

Cross-sector interactions have long occurred in the public delivery of goods, services, and interests. While scholars have often addressed cross-sector interactions using the dimensions of publicness (state) and privateness (market), an intersectoral framework necessitates the understanding and incorporation of nonprofitness to account for the dimensions of nonprofits along the public-private continuum. This article proposes a framework for identifying the dimensions of nonprofits in an intersectoral world and draws on relevant examples to illustrate the presence and influence of nonprofitness. The article then focuses on the future of education in the field of public administration and, in light of the proposed framework, makes and considers recommendations to help educational programs better equip students to appreciate work across sectors