Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis

To report on the identification of intrathecally synthesized immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to synapsin, a synaptic vesicle-associated protein, in a patient with limbic encephalitis

TO ERADICATION OF VOLTAGE SAG AND HARMONICS IN DISTRIBUTION SYSTEM USING DVR WITH CAPACITOR COMPENSATION SCHEME

Power Quality (PQ) is that the most vital perspectives on transmission and distribution ranges. The availability of high-grade electric powered offerings wished for the customers illustrates this idea. The voltage sag and swell square degree the most not unusual PQ problems that in particular rise up in the distribution systems because of the truth that it's going to cause tool tripping, failure of stress systems, closure for home and business instrumentality. The Dynamic Voltage Restorer (DVR) associated nonparallel has amazing dynamic talents and is a flexible solution for PQ troubles. Ultra-capacitors (UCAP) have quality developments like excessive strength and espresso electricity density important for the mitigation of voltage sag and swell. This paper offers AN extended DVR topology capable of handing over deep, prolonged mitigation for power terrific troubles. Within the planned DVR, UCAP is employed as strength storage because it offers immoderate electricity in a totally short c software language length of it gradual. The DVR is protected into Ultra capacitor via a bifacial DC-DC converter which facilitates in supplying a rigid dc-link voltage and conjointly enables in compensating transient voltage sag and voltage swell. PI Controller is hired in DVR for electricity exceptional improvement. The simulation model for the proposed device has been superior in MATLAB and therefore the performance over famous DVR is legitimate with the effects obtained

The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

Gemeinsames Vorkommen von VGLUT und VGAT auf synaptischen Vesikeln und in inhibitorischen und exzitatorischen Nervenendigungen

Synaptische Vesikel (SV) besitzen abhängig vom Neurontyp unterschiedliche Neurotransmittertransporter. In glutamatergen Neuronen kommen die vesikulären Glutamattransporter (VGLUT)1, VGLUT2 und VGLUT3 vor. GABAerge Neurone besitzen den vesikulären GABA-Transporter (VGAT). Die getrennte Glutamat- und GABA-Speicherung in unterschiedlichen Neuronen dient dem exakten Funktionieren neuronaler Netze. Mitunter setzen glutamaterge Neurone auch GABA frei. Einige entscheidende Proteine GABAerger Nervenendigungen wurden auf dem Protein- und mRNA-Niveau nachgewiesen. GABAerge Transmission glutamaterger Neurone wurde elektrophysiologisch gezeigt. Diese Studie untersucht eine mögliche VGLUT/VGAT-Kolokalisation mittels Immunisolierungen (II) von SV (SP), Neurotransmitteraufnahmeversuchen mit aufgereinigten SV, SP und der elektronenmikroskopischen Postembeddingmethode. II aus dem Rattengehirn zeigen, dass die VGLUT1-SP VGLUT2 und die VGLUT2-SP auch VGLUT1 enthält. Beide VGLUT kommen auf dem selben SV vor. Die VGLUT2-SP beinhaltet VGAT- und die VGAT-SP VGLUT2-tragende SV. SP aus frühen Entwicklungsstadien zeigen bereits eine ausgeprägte vesikuläre VGLUT2/VGAT- Kolokalisation. SV der VGAT-SP akkumulieren GABA und Glutamat. Die Hemmung der VGLUT zeigt ihren unterstützenden Einfluss auf die vesikuläre GABA- und Monoaminaufnahme. Damit moduliert die VGLUT-Aktivität die Neurotransmitterspeicherung in nicht glutamatergen Neuronen. Doppelmarkierung im Postembeddingverfahren zeigen die synaptische VGLUT/VGAT- Kolokalisation in glutamatergen hippokampalen und cerebellären Moosfaserendigungen. Dagegen ist VGAT weder in den nur VGLUT1-positiven cerebellären Parallelfaser- noch in den nur VGLUT2-positiven Kletterfaserendigungen detektierbar. Die cerebellären GABAergen Korbzellenendigungen beinhalten auch VGLUT2. Diese Befunde liefern den morphologischen Beweis für die synaptische GABA/Glutamat-Koausschüttung aus speziellen großen glutamatergen und GABAergen präsynaptischen Endigungen.Synaptic vesicles (SV) are equipped with a common set of proteins. Dependent on the type of nerve cell SV differ in their neurotransmitter transporters, i.e. the vesicular glutamate transporters (VGLUT) 1 and VGLUT2 in types of glutamatergic neurons and the vesicular GABA transporter (VGAT) in types of GABAergic neurons. The strict separation of glutamate and GABA storage generally guarantees the precise function of neuronal networks. However, GABA may be released by glutamatergic neurons under certain conditions as shown by electrophysiological studies. The project aims to analyse a putative vesicular and synaptic co-localisation of VGLUT and VGAT using immunoisolations, neurotransmitter uptake assays, and post-embedding electron microscopy. Immunoisolations from whole brain of adult rats revealed that VGLUT1 immunoisolates (ii) contain VGLUT2 and VGLUT2-ii also have VGLUT1 indicating the vesicular co-localisation of both VGLUT. VGLUT2-ii harbour in addition VGAT and VGAT-ii also contain VGLUT2. Transporter-specific ii from rat brain at different postnatal levels (P5/15/30) show a pronounced vesicular co-localisation of VGLUT2 and VGAT during these early developmental stages. Transmitter uptake studies show GABA and also glutamate concentrating VGAT-ii. Using the specific inhibitor trypan blue we found that VGLUT activity improves GABA as well as monoamine uptake into SV. Thus VGLUT activity modulates transmitter storage in non-glutamatergic neurons. Post-embedding immunogold double labelling indicates a synaptic co-localisation of VGLUT and VGAT in glutamatergic hippocampal and cerebellar mossy fibre terminals while VGAT was not seen in cerebellar parallel fibre (VGLUT1-positive only) and climbing fibre (VGLUT2-positive only) terminals. Remarkably, cerebellar GABAergic basket cell terminals also contain VGLUT2. These findings provide the morphological evidence for a synaptic co-release of GABA and glutamate from some large glutamatergic and GABAergic terminals

Co-existence of functionally different vesicular neurotransmitter transporters

The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes. VGLUTs concentrate the excitatory amino acid glutamate, VGAT the inhibitory amino acid GABA, VMAT2 monoamines, and VAChT acetylcholine into synaptic vesicle (SV). Following membrane depolarization SV release their content into the synaptic cleft. A strict segregation of vesicular transporters is mandatory for the precise functioning of synaptic communication and of neuronal circuits. In the last years, evidence accumulates that subsets of neurons express more than one of these transporters leading to synaptic co-release of different and functionally opposing transmitters and modulation of synaptic plasticity. Synaptic co-existence of transporters may change during pathological scenarios in order to ameliorate misbalances in neuronal activity. In addition, evidence increases that transporters also co-exist on the same vesicle providing another layer of regulation. Generally, vesicular transmitter loading relies on an electrochemical gradient µH+ driven by the proton ATPase rendering the lumen of the vesicle with respect to the cytosol positive () and acidic (pH). While the activity of VGLUT mainly depends on the component, VMAT, VGAT and VAChT work best at a high pH. Thus, a vesicular synergy of transporters depending on the combination may increase or decrease the filling of SV with the principal transmitter. We provide an overview on synaptic co-existence of vesicular transmitter transporters including changes in the excitatory/inhibitory balance under pathological conditions. Additionally, we discuss functional aspects of vesicular synergy of transmitter transporters

Serotonin Transporter Associated Protein Complexes Are Enriched in Synaptic Vesicle Proteins and Proteins Involved in Energy Metabolism and Ion Homeostasis

The serotonin transporter (SERT) mediates Na⁺-dependent high-affinity serotonin uptake and plays a key role in regulating extracellular serotonin concentration in the brain and periphery. To gain novel insight into SERT regulation, we conducted a comprehensive proteomics screen to identify components of SERT-associated protein complexes in the brain by employing three independent approaches. In vivo SERT complexes were purified from rat brain using an immobilized high-affinity SERT ligand, amino-methyl citalopram. This approach was combined with GST pulldown and yeast two-hybrid screens using N- and C-terminal cytoplasmic transporter domains as bait. Potential SERT associated proteins detected by at least two of the interaction methods were subjected to gene ontology analysis resulting in the identification of functional protein clusters that are enriched in SERT complexes. Prominent clusters include synaptic vesicle proteins, as well as proteins involved in energy metabolism and ion homeostasis. Using subcellular fractionation and electron microscopy we provide further evidence that SERT is indeed associated with synaptic vesicle fractions, and colocalizes with small vesicular structures in axons and axon terminals. We also show that SERT is found in close proximity to mitochondrial membranes in both, hippocampal and neocortical regions. We propose a model of the SERT interactome, in which SERT is distributed between different subcellular compartments through dynamic interactions with site-specific protein complexes. Finally, our protein interaction data suggest novel hypotheses for the regulation of SERT activity and trafficking, which ultimately impact on serotonergic neurotransmission and serotonin dependent brain functions

Regulation of the Hippocampal Network by VGLUT3-Positive CCK- GABAergic Basket Cells

International audienceHippocampal interneurons release the inhibitory transmitter GABA to regulate excitation, rhythm generation and synaptic plasticity. A subpopulation of GABAergic basket cells co-expresses the GABA/glycine vesicular transporters (VIAAT) and the atypical type III vesicular glutamate transporter (VGLUT3); therefore, these cells have the ability to signal with both GABA and glutamate. GABAergic transmission by basket cells has been extensively characterized but nothing is known about the functional implications of VGLUT3-dependent glutamate released by these cells. Here, using VGLUT3-null mice we observed that the loss of VGLUT3 results in a metaplastic shift in synaptic plasticity at Shaeffer’s collaterals - CA1 synapses and an altered theta oscillation. These changes were paralleled by the loss of a VGLUT3-dependent inhibition of GABAergic current in CA1 pyramidal layer. Therefore presynaptic type III metabotropic could be activated by glutamate released from VGLUT3-positive interneurons. This putative presynaptic heterologous feedback mechanism inhibits local GABAergic tone regulates the hippocampal neuronal network