Cognitive Impairment in Neuromyelitis Optica Spectrum Disorders: A Review of Clinical and Neuroradiological Features

Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing autoimmune inflammatory disorders of the central nervous system (CNS) with optic neuritis, myelitis, and brainstem syndromes as clinical hallmarks. With a reported prevalence of up to 70%, cognitive impairment is frequent, but often unrecognized and an insufficiently treated burden of the disease. The most common cognitive dysfunctions are decline in attention andmemory performance.Magnetic resonance imaging can be used to access structural correlates of neuropsychological disorders. Cognitive impairment is not only a highly underestimated symptom in patients with NMOSD, but potentially also a clinical correlate of attack-independent changes in NMOSD, which are currently under debate. This article reviews cognitive impairment in NMOSD and discusses associations between structural changes of the CNS and cognitive deficits

Calcium binding to a disordered domain of a type III-secreted protein from a coral pathogen promotes secondary structure formation and catalytic activity

Strains of the Gram-negative bacterium Vibrio coralliilyticus cause the bleaching of corals due to decomposition of symbiotic microalgae. The V. coralliilyticus strain ATCC BAA-450 (Vc450) encodes a type III secretion system (T3SS). The gene cluster also encodes a protein (locus tag VIC_001052) with sequence homology to the T3SS-secreted nodulation proteins NopE1 and NopE2 of Bradyrhizobium japonicum (USDA110). VIC_001052 has been shown to undergo auto-cleavage in the presence of Ca2+ similar to the NopE proteins. We have studied the hitherto unknown secondary structure, Ca2+-binding affinity and stoichiometry of the "metal ion-inducible autocleavage" (MIIA) domain of VIC_001052 which does not possess a classical Ca2+-binding motif. CD and fluorescence spectroscopy revealed that the MIIA domain is largely intrinsically disordered. Binding of Ca2+ and other di- and trivalent cations induced secondary structure and hydrophobic packing after partial neutralization of the highly negatively charged MIIA domain. Mass spectrometry and isothermal titration calorimetry showed two Ca2+-binding sites which promote structure formation with a total binding enthalpy of -110 kJ mol(-1) at a low micromolar K-d. Putative binding motifs were identified by sequence similarity to EF-hand domains and their structure analyzed by molecular dynamics simulations. The stoichiometric Ca2+-dependent induction of structure correlated with catalytic activity and may provide a "host-sensing" mechanism that is shared among pathogens that use a T3SS for efficient secretion of disordered proteins

Constructive approach to limiting periodic orbits with exponential and power law dynamics

In dynamical systems limit cycles arise as a result of a Hopf bifurcation, after a control parameter has crossed its critical value. In this study we present a constructive method to produce dissipative dynamics which lead to stable periodic orbits as time grows, with predesigned transient dynamics. Depending on the construction method a) the limiting orbit can be a regular circle, an ellipse or a more complex closed orbit and b) the approach to the limiting orbit can follow an exponential law or a power law. This technique allows to design nonlinear models of dynamical systems with desired (exponential or power law) relaxation properties.Comment: 17 pages, 6 figure

The effect of ultra-thin graphite on the morphology and physical properties of thermoplastic polyurethane elastomer composites

[EN] Composites of thermoplastic polyurethane (TPU) and ultra-thin graphite (UTG) with concentrations ranging from 0.5 wt.% to 3 wt.% were prepared using a solution compounding strategy. Substantial reinforcing effects with increased loadings are achieved. Compared to neat TPU, values for storage modulus and shear viscosity are enhanced by 300% and 150%, respectively, for UTG concentrations of 3 wt.%. Additionally, an enhancement of thermal properties is accomplished. The crystallization temperature and thermal stability increased by 30 C and 10 C, respectively, compared to neat TPU. Furthermore, the use of oxidized UTG (UTGO) with its added functional oxygen groups suggests the presence of chemical interactions between UTG and TPU, which additionally impact on the thermal properties of the corresponding composites. Controlling the oxidation degree, thus offers further possibilities to obtain composites with tailored properties. The presented approach is straightforward, leads to homogeneous TPU-UTG composites with improved materials properties and is especially suitable for commercial UTG materials and further up-scaled production.This research was supported by IMPIVA under Project (IMIDIP/2010/58), Spanish Ministry of Science and Innovation (MICINN) under Project MAT2010-15026, CSIC under Project 201080E124, and the Government of Aragon (DGA) and the European Social Fund (ESF) under Project DGA-ESF-T66 CNN. M.C. thanks MICINN and ESF for her Grant No. BES-2008-003503. Authors thank Merquinsa S.L. (Barcelona, Spain) and Avanzare S.L. (La Rioja, Spain) for kindly providing polyurethane and ultra-thin graphite samples, respectively.Menes, O.; Cano, M.; Benedito, A.; Giménez Torres, E.; Castell, P.; Maser, WK.; Benito, AM. (2012). The effect of ultra-thin graphite on the morphology and physical properties of thermoplastic polyurethane elastomer composites. Composites Science and Technology. 72(13):1595-1601. https://doi.org/10.1016/j.compscitech.2012.06.016S15951601721

The OSCAR-MP Consensus Criteria for Quality Assessment of Retinal Optical Coherence Tomography Angiography

Background and Objectives Optical coherence tomography angiography (OCTA) is a noninvasive high-resolution imaging technique for assessing the retinal vasculature and is increasingly used in various ophthalmologic, neuro-ophthalmologic, and neurologic diseases. To date, there are no validated consensus criteria for quality control (QC) of OCTA. Our study aimed to develop criteria for OCTA quality assessment. Methods To establish criteria through (1) extensive literature review on OCTA artifacts and image quality to generate standardized and easy-to-apply OCTA QC criteria, (2) application of OCTA QC criteria to evaluate interrater agreement, (3) identification of reasons for interrater disagreement, revision of OCTA QC criteria, development of OCTA QC scoring guide and training set, and (4) validation of QC criteria in an international, interdisciplinary multicenter study. Results We identified 7 major aspects that affect OCTA quality: (O) obvious problems, (S) signal strength, (C) centration, (A) algorithm failure, (R) retinal pathology, (M) motion artifacts, and (P) projection artifacts. Seven independent raters applied the OSCAR-MP criteria to a set of 40 OCTA scans from people with MS, Sjogren syndrome, and uveitis and healthy individuals. The interrater kappa was substantial (κ 0.67). Projection artifacts were the main reason for interrater disagreement. Because artifacts can affect only parts of OCTA images, we agreed that prior definition of a specific region of interest (ROI) is crucial for subsequent OCTA quality assessment. To enhance artifact recognition and interrater agreement on reduced image quality, we designed a scoring guide and OCTA training set. Using these educational tools, 23 raters from 14 different centers reached an almost perfect agreement (κ 0.92) for the rejection of poor-quality OCTA images using the OSCAR-MP criteria. Discussion We propose a 3-step approach for standardized quality control: (1) To define a specific ROI, (2) to assess the occurrence of OCTA artifacts according to the OSCAR-MP criteria, and (3) to evaluate OCTA quality based on the occurrence of different artifacts within the ROI. OSCAR-MP OCTA QC criteria achieved high interrater agreement in an international multicenter study and is a promising QC protocol for application in the context of future clinical trials and studies

The OSCAR-MP Consensus Criteria for Quality Assessment of Retinal Optical Coherence Tomography Angiography

BACKGROUND AND OBJECTIVES: Optical coherence tomography angiography (OCTA) is a noninvasive high-resolution imaging technique for assessing the retinal vasculature and is increasingly used in various ophthalmologic, neuro-ophthalmologic, and neurologic diseases. To date, there are no validated consensus criteria for quality control (QC) of OCTA. Our study aimed to develop criteria for OCTA quality assessment. METHODS: To establish criteria through (1) extensive literature review on OCTA artifacts and image quality to generate standardized and easy-to-apply OCTA QC criteria, (2) application of OCTA QC criteria to evaluate interrater agreement, (3) identification of reasons for interrater disagreement, revision of OCTA QC criteria, development of OCTA QC scoring guide and training set, and (4) validation of QC criteria in an international, interdisciplinary multicenter study. RESULTS: We identified 7 major aspects that affect OCTA quality: (O) obvious problems, (S) signal strength, (C) centration, (A) algorithm failure, (R) retinal pathology, (M) motion artifacts, and (P) projection artifacts. Seven independent raters applied the OSCAR-MP criteria to a set of 40 OCTA scans from people with MS, Sjogren syndrome, and uveitis and healthy individuals. The interrater kappa was substantial (κ 0.67). Projection artifacts were the main reason for interrater disagreement. Because artifacts can affect only parts of OCTA images, we agreed that prior definition of a specific region of interest (ROI) is crucial for subsequent OCTA quality assessment. To enhance artifact recognition and interrater agreement on reduced image quality, we designed a scoring guide and OCTA training set. Using these educational tools, 23 raters from 14 different centers reached an almost perfect agreement (κ 0.92) for the rejection of poor-quality OCTA images using the OSCAR-MP criteria. DISCUSSION: We propose a 3-step approach for standardized quality control: (1) To define a specific ROI, (2) to assess the occurrence of OCTA artifacts according to the OSCAR-MP criteria, and (3) to evaluate OCTA quality based on the occurrence of different artifacts within the ROI. OSCAR-MP OCTA QC criteria achieved high interrater agreement in an international multicenter study and is a promising QC protocol for application in the context of future clinical trials and studies

Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1

Peer reviewe

A novel glycine receptor splice variant predicts unorthodox transmembrane topology: assembly into heteromeric receptor complexes

Der Glycinrezeptor (GlyR) ist ein ligandengesteuerter Clˉ-Kanal aus der Familie der Cys-Loop-Rezeptoren und einer der wichtigsten Vermittler der schnellen synaptischen Inhibition in Rückenmark und Hirnstamm. Der Ionenkanal besteht aus zwei α- und drei β-Untereinheiten, die einen pentameren, rosettenförmigen Proteinkomplex bilden. Während die Variabilität der GlyR α-Untereinheiten durch alternative Spleißvorgänge entscheidend erhöht wird, sind bislang von der β-Untereinheit keine Spleißvarianten bekannt. Die vorliegende Arbeit beschreibt eine neue Spleißvariante der β-Untereinheit des GlyRs, die durch alternatives Spleißen zur Erhöhung der Variabilität dieser Rezeptor-Untereinheit beiträgt. Die Zielstellung bestand in der Charakterisierung dieser neu identifizierten Spleißvariante der β-Untereinheit des GlyRs sowohl auf Transkriptebene, als auch auf Proteinniveau. Im Vergleich zur Wildtyp GlyR β-Untereinheit liegt dieser Variante eine durch alternatives Spleißen hervorgerufene Deletion der Aminosäurepositionen 252-301 zugrunde, welche exakt durch das Exon 7 des Glrb-Gens kodiert werden (β∆7). Das Fehlen von Exon 7 führt zu einer Verkürzung am 3’-Ende des extrazellulär lokalisierten N-Terminus um 14 Aminosäuren, dem vollständigen Verlust der Transmembrandomäne 1 (TM1), der intrazellulären Schleife zwischen TM1 und TM2 und den ersten vier Aminosäuren der TM2. Dieses endogen vorkommende Transkript wurde überwiegend in Astroglia-Zellen und in nicht-neuronalen Geweben (Leber und Herz) von B6+/+-Wildtyp Mäusen nachgewiesen. Durch verschiedenste Expressionsstudien in HEK293- und Cos7-, sowie primären neuronalen Zellkulturen konnte die Integration des β∆7-Polypeptides unabhängig von der α1-Untereinheit des GlyRs in die Plasmamemban gezeigt werden. Anhand von Immunpräzipitationsstudien wurde die Assemblierung mit der α1-Untereinheit und mit dem intrazellulären Ankerprotein Gephyrin zu stabilen Proteinkomplexen nachgewiesen. Demgegenüber belegen die elektrophysio-logischen Untersuchungen der α1/β∆7-heteromeren Rezeptorkomplexe eine durch Picrotoxin vermittelte Blockierung des Ionenkanals ähnlich der von α1 Homomeren. Somit bildet die neue β-Spleißvariante keinen funktionellen Ionenkanal aus. Weiterhin führten die gewonnenen Erkenntnisse zur Aufstellung eines neuen Topologie-Modells für diese Variante, welches von dem bislang allgemein gültigen der Cys-Loop-Rezeptorfamilie verschiedenen ist. 1. Summary The glycine receptor (GlyR) is a ligand gated chloride channel of the cys-loop-receptor family. Glycine is one of the most important mediators of the fast synaptic inhibition in spinal cord and brainstem. The ion channel consists of 2α- and 3β-subunits, which form a pentameric, donut-like protein complex. While the variability of the α-subunit is enhanced by alternative splicing processes, no splice variants of the β-subunit are described, so far. The present work characterizes a novel splice variant of the β-subunit of the GlyR, which contributes to the variability of this receptor subunit. The general aim was a detailed study of the recently identified new splice variant of the GlyR β-subunit, both at the transcript and the protein level. In comparison to wildtype that variant shows a deletion of amino acid positions 252-301 encoded exactly by exon 7 of the Glrb-gene (β∆7). The absence of exon 7 results in a truncation of the 3’-end at the extracellular N-terminus by 14 amino acids, the complete loss of transmembrane domain 1 (TM1), the extracellular loop between TM1 and TM2 and the first 4 amino acids of TM2. The endogeneously present transcript was detected mainly in astroglial cells and non-neuronal tissues (liver, heart) of B6+/+-wildtype mice. Various expression systems, such as HEK293-, Cos7- and primary neuronal cell cultures demonstrated that the β∆7-polypeptide is able to integrate into the plasmamembrane independent of the α1-subunit of the GlyR. Using immunoprecipitation studies, the assembly with the α1-subunit and the intracellular anchor protein gephyrin into stable protein complexes was shown. Electrophysiological studies, however, demonstrated that α1/β∆7-heteromeric receptor complexes are similarly blocked by picrotoxin as α1-homomeres. Hence, the new splice variant does not contribute a functional ion channel domain. The obtained results lead to a postulation of a new model for the topology of the β∆7 variant, which differs from the common topology model present for cys-loop-receptors.The glycine receptor (GlyR) is a ligand gated chloride channel of the cys-loop-receptor family. Glycine is one of the most important mediators of the fast synaptic inhibition in spinal cord and brainstem. The ion channel consists of 2α- and 3β-subunits, which form a pentameric, donut-like protein complex. While the variability of the α-subunit is enhanced by alternative splicing processes, no splice variants of the β-subunit are described, so far. The present work characterizes a novel splice variant of the β-subunit of the GlyR, which contributes to the variability of this receptor subunit. The general aim was a detailed study of the recently identified new splice variant of the GlyR β-subunit, both at the transcript and the protein level. In comparison to wildtype that variant shows a deletion of amino acid positions 252-301 encoded exactly by exon 7 of the Glrb-gene (β∆7). The absence of exon 7 results in a truncation of the 3’-end at the extracellular N-terminus by 14 amino acids, the complete loss of transmembrane domain 1 (TM1), the extracellular loop between TM1 and TM2 and the first 4 amino acids of TM2. The endogeneously present transcript was detected mainly in astroglial cells and non-neuronal tissues (liver, heart) of B6+/+-wildtype mice. Various expression systems, such as HEK293-, Cos7- and primary neuronal cell cultures demonstrated that the β∆7-polypeptide is able to integrate into the plasmamembrane independent of the α1-subunit of the GlyR. Using immunoprecipitation studies, the assembly with the α1-subunit and the intracellular anchor protein gephyrin into stable protein complexes was shown. Electrophysiological studies, however, demonstrated that α1/β∆7-heteromeric receptor complexes are similarly blocked by picrotoxin as α1-homomeres. Hence, the new splice variant does not contribute a functional ion channel domain. The obtained results lead to a postulation of a new model for the topology of the β∆7 variant, which differs from the common topology model present for cys-loop-receptors

Longitudinal analysis of primary and secondary factors related to fatigue in multiple sclerosis

Purpose!#!Investigation of the current practice of diagnostics and treatment in pediatric cancer patients with febrile neutropenia.!##!Methods!#!On behalf of the German Society for Pediatric Oncology and Hematology and the German Society for Pediatric Infectious Diseases, an Internet-based survey was conducted in 2016 concerning the management of febrile neutropenia in pediatric oncology centers (POC). This survey accompanied the release of the corresponding German guideline to document current practice before its implementation in clinical practice.!##!Results!#!In total, 51 POCs participated (response rate 73%; 43 from Germany, and 4 each from Austria and Switzerland). Identified targets for antimicrobial stewardship concerned blood culture diagnostics, documentation of the time to antibiotics, the use of empirical combination therapy, drug monitoring of aminoglycosides, the time to escalation in patients with persisting fever, minimal duration of IV treatment, sequential oral treatment in patients with persisting neutropenia, indication for and choice of empirical antifungal treatment, and the local availability of a pediatric infectious diseases consultation service.!##!Conclusion!#!This survey provides useful information for local antibiotic stewardship teams to improve the current practice referring to the corresponding national and international guidelines

DNA Based Formation of Nanodisc-Stacks

We describe here the formation of multimers of membrane-scaffolding protein MSP1D1-bounded nanodiscs using the thiol reactivity of engineered cysteines. The mutated positions N42 and K163 in MSP1D1 were chosen to support chemical modification as evidenced by fluorescent labeling with pyrene. The direct disulphide bond formation of nanodiscs formed by the MSP1D1_N42C variant led to dimers and trimers with low yield. In contrast, transmission electron microscopy revealed that the attachment of oligonucleotides to the engineered cysteines of MSP1D1 allowed the growth of submicron-sized tracts of stacked nanodiscs through the hybridization of nanodisc populations carrying complementary strands and a flexible spacer