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News Article | April 26, 2017
Site: www.eurekalert.org

AURORA, Colo. (April 26, 2017) - Using a unique microscope capable of illuminating living cell structures in great detail, researchers at the University of Colorado Anschutz Medical Campus have found clues into how a destructive autoimmune disease works, setting the stage for more discoveries in the future. The scientists were trying to visualize antibodies that cause neuromyelitis optica (NMO), a rare autoimmune disorder that results in paralysis and blindness. Using a custom STED (Stimulated Emission Depletion) microscope built at CU Anschutz, they were able to actually see clusters of antibodies atop astrocytes, the brain cell target of the autoimmune response in NMO. "We discovered that we could see the natural clustering of antibodies on the surface of target cells. This could potentially correspond with their ability to damage the cells," said Professor Jeffrey Bennett, MD, PhD, senior author of the study and associate director of Translational Research at the Center for NeuroScience at CU Anschutz. "We know that once antibody binds to the surface of the astrocyte, we are witnessing the first steps in the disease process." When that domino effect begins, it's hard to stop. But Bennett said the ability to see the antibodies on the brain cells offers a chance to develop targeted therapies that do not suppress the body's immune system like current treatments for the disease do. "By applying this novel approach we can see firsthand how these antibodies work," said the study's lead author, John Soltys, a current student in the Medical Scientist Training Program at CU Anschutz. "We are looking at the initiation of autoimmune injury in this disease." The breakthrough was made possible with the STED microscope, a complex instrument that uses lasers to achieve extreme precision and clarity. It was built by physicist Stephanie Meyer, PhD, at CU Anschutz. This is the first time it has been used in a research project here. "This would have been impossible to see with any kind of normal microscope," said study co-author Professor Diego Restrepo, PhD, director of the Center for NeuroScience. "We are inviting other scientists with research projects on campus to use the STED microscope." According to Meyer, lower resolution microscopes are blurrier than the STED due to diffraction of light. But the STED's lasers illuminate a smaller area to acquire a higher resolution image. Unlike electron microscopes, STED users can see entire living cells at extremely high resolution, as they did in this study. Restrepo said there are only a handful of STEDs in the nation and just one in Colorado. The researchers said the discovery is the result of a unique partnership between clinical neurology, immunology and neuroscience coming together to solve a fundamental question of how antibodies can initiate targeted injury in an autoimmune disease. "These are the building blocks that we can use to carry our research to the next level," Bennett said. The study was published this week in Biophysical Journal.


News Article | April 26, 2017
Site: www.rdmag.com

A new type of microscope, capable of illuminating living cell structures in clear detail, could provide insight into autoimmune diseases and lead to new treatment options. Researchers from the University of Colorado Anschutz Medical Campus believe this new tool— a custom Stimulated Emission Depletion (STED) microscope—could set the stage for future treatment discoveries and visualize antibodies that cause the rare autoimmune disorder neuromyelitis optica, which can result in paralysis and blindness. The researchers used the microscope to actually see the clusters of antibodies atop astrocytes—the brain cell target of the autoimmune response in the disease. “By applying this novel approach we can see firsthand how these antibodies work,” the study's lead author, John Soltys, a current student in the Medical Scientist Training Program at CU Anschutz, said in a statement. “We are looking at the initiation of autoimmune injury in this disease.” Dr. Jeffrey Bennett, Ph.D., the senior author of the study and the associate director of Translational Research at the Center for NeuroScience at CU Anschutz, explained that the microscope allows researchers to view the early stages of various diseases as they form. “We discovered that we could see the natural clustering of antibodies on the surface of target cells,” Bennett said in a statement. “This could potentially correspond with their ability to damage the cells. “We know that once antibody binds to the surface of the astrocyte, we are witnessing the first steps in the disease process,” he added. According to Bennett, the ability to see the antibodies on the brain cells offers researchers an opportunity to develop targeted therapies that do not suppress the body’s immune system like some current treatments for the disease do. The STED microscope—which was built by CU Anschutz physicist Stephanie Meyer, Ph.D.—uses lasers to achieve a higher level of precision and clarity. Lower resolution microscopes are blurry because of the diffraction of light. However, the lasers illuminate a smaller area to acquire a higher resolution image than traditional microscopes. The STED microscope can also highlight entire living cells at extremely high resolution, unlike electron microscopes. “This would have been impossible to see with any kind of normal microscope,” professor Diego Restrepo, Ph.D., director of the Center for NeuroScience and study co-author, said in a statement. “We are inviting other scientists with research projects on campus to use the STED microscope.” The study was published in Biophysical Journal.


Ma X.,Genentech | Lin W.Y.,Genentech | Chen Y.,Genentech | Stawicki S.,Genentech | And 6 more authors.
Structure | Year: 2012

Lacking any discernible sequence similarity, interleukin-34 (IL-34) and colony stimulating factor 1 (CSF-1) signal through a common receptor CSF-1R on cells of mononuclear phagocyte lineage. Here, the crystal structure of dimeric IL-34 reveals a helical cytokine fold homologous to CSF-1, and we further show that the complex architecture of IL-34 bound to the N-terminal immunoglobulin domains of CSF-1R is similar to the CSF-1/CSF-1R assembly. However, unique conformational adaptations in the receptor domain geometry and intermolecular interface explain the cross-reactivity of CSF-1R for two such distantly related ligands. The docking adaptations of the IL-34 and CSF-1 quaternary complexes, when compared to the stem cell factor assembly, draw a common evolutionary theme for transmembrane signaling. In addition, the structure of IL-34 engaged by a Fab fragment reveals the mechanism of a neutralizing antibody that can help deconvolute IL-34 from CSF-1 biology, with implications for therapeutic intervention in diseases with myeloid pathogenic mechanisms. © 2012 Elsevier Ltd.


Asherson P.,King's College London | Bushe C.,Eli Lilly and Company | Saylor K.,Neuroscience Inc. | Tanaka Y.,Eli Lilly and Company | And 2 more authors.
Journal of Psychopharmacology | Year: 2014

Persistence of attention deficit hyperactivity disorder (ADHD) into adulthood can be disabling or lead to substantial impairment. Several clinical trials of atomoxetine (ATX) in adults with ADHD have been reported following the National Institute for Health and Clinical Excellence (NICE) guidelines issued in 2008. We performed an integrated analysis of all Eli Lilly-sponsored, randomized, double-blind, placebo-controlled studies of ATX in adults with ADHD completed as of May 2012. Individual patient data were pooled from six short-term (10-16 week) studies (1961 patients) and three longer-term (six-month) studies (1413 patients). In the short-term analysis, ATX patients achieved a significantly greater mean reduction in ADHD symptoms than placebo patients (-12.2 vs -8.1; Conners' Adult ADHD Rating Scale-Investigator-Rated: Screening Version (CAARS-Inv: SV); p<0.001). In the longer-term analysis, respective improvements after six months were -13.2 vs -9.7 (p<0.001). Response rates at study endpoints for ATX vs placebo, based on CAARS-Inv: SV improvement ≥30% and Clinical Global Impressions of ADHD-Severity (CGI-ADHD-S) ≥3 were 34.8% vs 22.3% in the short-term and 43.4% vs 28.0% after six months, and CAARS-Inv: SV improvements ≥40% were 41.3% vs 25.3% in the short-term and 44.0% vs 31.4% after six months (all p<0.001). Overall, ATX had a clinically significant effect in adults with ADHD, with reductions in core symptoms and clinically meaningful responder rates. © The Author(s) 2014.


Vojdani A.,Immunosciences Laboratory Inc. | Lambert J.,Immunosciences Laboratory Inc. | Kellermann G.,NeuroScience Inc.
Evidence-based Complementary and Alternative Medicine | Year: 2011

Abundant research has mapped the inflammatory pathways leading to autoimmunity and neuroinflammatory disorders. The latest T helper to be identified, Th17, through its proinflammatory cytokine IL-17, plays a pathogenic role in many inflammatory conditions. Today, healthcare providers have a wealth of anti-inflammatory agents from which to choose. On one hand, pharmaceutical companies market brand-name drugs direct to the public and physicians. Medical botanical knowledge, on the other hand, has been passed down from generation to generation. The demands for natural healing therapies have brought corresponding clinical and laboratory research studies to elucidate the medicinal properties of alternative practices. With a variety of options, it can be difficult to pinpoint the proper anti-inflammatory agent for each case presented. In this review, the authors highlight a vast array of anti-inflammatory medicaments ranging from drugs to vitamins and from botanicals to innate molecules. This compilation may serve as a guide for complimentary and alternative healthcare providers who need to target neuroinflammation driven by Th17 and its inflammatory cytokine IL-17. By understanding the mechanisms of anti-inflammatory agents, CAM practitioners can tailor therapeutic interventions to fit the needs of the patient, thereby providing faster relief from inflammatory complaints. Copyright © 2011 Aristo Vojdani et al.


Nichkova M.,Pharmasan Labs Inc. | Wynveen P.M.,Pharmasan Labs Inc. | Marc D.T.,NeuroScience Inc. | Huisman H.,Pharmasan Labs Inc. | Kellermann G.H.,NeuroScience Inc.
Journal of Neurochemistry | Year: 2013

Dopamine is a catecholamine that serves as a neurotransmitter in the central and peripheral nervous system. Non-invasive, reliable, and high-throughput techniques for its quantification are needed to assess dysfunctions of the dopaminergic system and monitor therapies. We developed and validated a competitive ELISA for direct determination of dopamine in urine samples. The method provides high specificity, good accuracy, and precision (average inter-assay variation < 12%). The analysis is not affected by general urinary components and structurally related drugs and metabolites. The correlation between ELISA and LC-MS/MS analyses was very good (r = 0.986, n = 28). The reference range was 64-261 μg/g Cr (n = 64). Week-to-week biological variations of second morning urinary dopamine under free-living conditions were 23.9% for within- and 35.5% for between-subject variation (n = 10). The assay is applied in monitoring Parkinson's disease patients under different treatments. Urinary dopamine levels significantly increase in a dose-dependent manner for Parkinson's disease patients under l-DOPA treatment. The present ELISA provides a cost-effective alternative to chromatographic methods to monitor patients receiving dopamine restoring treatment to ensure appropriate dosing and clinical efficacy. The method can be used in pathological research for the assessment of possible peripheral biological markers for disorders related to the dopaminergic system. Our competitive ELISA for direct dopamine quantification in urine samples is a viable cost-effective alternative to chromatographic analysis. The method is robust, sensitive, and very specific and it does not require sample pre-treatment. It can be used in monitoring dopamine-modulating therapies. Urinary dopamine levels significantly increase in a dose-dependent manner for Parkinson's disease patients under l-DOPA treatment. © 2013 International Society for Neurochemistry.


Huisman H.,Pharmasan Laboratories Inc. | Wynveen P.,Pharmasan Laboratories Inc. | Nichkova M.,Pharmasan Laboratories Inc. | Kellermann G.,Pharmasan Laboratories Inc. | Kellermann G.,NeuroScience Inc.
Analytical Chemistry | Year: 2010

The inhibitory neurotransmitters GABA, glycine and agmatine and neuromodulators β-phenylethylamine (β-PEA) and taurine are important biogenic amines of the sympathetic and parasympathetic nervous systems in the body. Abnormalities in the metabolism of these biomarkers have been implicated in a vast number of neurological diseases. Novel competitive immunoassays, using one unique whole urine derivatization procedure applicable for all five biomarkers, have been developed. The determination of these biomarkers was highly reproducible: the coefficient of variance of inter- and intra-assay variation is between 3.9% and 9.8% for all assays. The assays show a good linearity in urine samples within the range of 100-400 mg Cr/dL and specificity when urine samples are spiked with biogenic amines. The recoveries are between 76 and 154%. The correlation between HPLC and ELISA for glycine and taurine (n = 10) showed regression coefficients of 0.97 and 0.98, respectively. An in vivo study on the urinary clearance of β-PEA, agmatine and taurine after oral intake by healthy individuals demonstrated the specificity and clinical significance of these new immunoassays. The immunoassays are useful for clinical and basic research where a fast and accurate assay for the screening of biogenic amines in urine is required, without preclearance of the sample. © 2010 American Chemical Society.


Kheirandish-Gozal L.,University of Chicago | McManus C.J.T.,NeuroScience Inc. | Kellermann G.H.,NeuroScience Inc. | Samiei A.,University of Chicago | Gozal D.,University of Chicago
Chest | Year: 2013

Background: Pediatric obstructive sleep apnea (OSA) is associated with cognitive dysfunction, suggesting altered neurotransmitter function. We explored overnight changes in neurotransmitters in the urine of children with and without OSA. Methods: Urine samples were collected from children with OSA and from control subjects before and after sleep studies. A neurocognitive battery assessing general cognitive ability (GCA) was administered to a subset of children with OSA. Samples were subjected to multiple enzyme-linked immunosorbent assays for 12 neurotransmitters, and adjusted for creatinine concentrations. Results: The study comprised 50 children with OSA and 20 control subjects. Of the children with OSA, 20 had normal GCA score (mean ± SD) (101.2 ± 14.5) and 16 had a reduced GCA score (87.3 ± 13.9; P<.001). Overnight increases in epinephrine, norepinephrine, and γ-aminobutyric acid (GABA) levels emerged in children with OSA; taurine levels decreased. Using combinatorial approaches and cutoff values for overnight changes of these four neurotransmitters enabled prediction of OSA (area under the curve [AUC]: 0.923; P<.0001). Furthermore, GABA and taurine alterations, as well as overnight reductions in phenylethylamine, were more prominent in children with OSA and low GCA than in children with OSA and normal GCA (P<.001), and they reliably discriminated GCA status (AUC: 0.977; P<.0001). Conclusions: Pediatric OSA is associated with overnight increases in urinary concentrations of catecholamines indicative of heightened sympathetic outflow. Increases in GABA levels and decreases in taurine levels could underlie mechanisms of neuronal excitotoxicity and dysfunction. Combinatorial approaches using defined cutoffs in overnight changes in concentrations of selected neurotransmitters in urine may not only predict OSA but also the presence of cognitive deficits. Larger cohort studies appear warranted to confirm these findings. © 2013 American College of Chest Physicians.


Troutman T.D.,University of Texas Southwestern Medical Center | Bazan J.F.,NeuroScience Inc. | Pasare C.,University of Texas Southwestern Medical Center
Cell Cycle | Year: 2012

TLRs are a family of pattern recognition receptors that recognize conserved molecular structures/products from a wide variety of microbes.1,2Following recognition of ligands, TLRs recruit signaling adapters to initiate a pro-inflammatory signaling cascade culminating in the activation of several transcription factor families. Additionally, TLR signals lead to activation of PI3K, affecting many aspects of the cellular response, including cell survival, proliferation and regulation of the pro-inflammatory response.3-10 The recent discovery of BCAP as a TLR signaling adaptor, crucial for linking TLRs to PI3K activation, allows new questions of the importance of PI3K activation downstream of TLRs. Here, we summarize the current understanding of signaling pathways activated by TLRs and provide our perspective on TLR mediated activation of PI3K and its impact on regulating cellular processes. © 2012 Landes Bioscience.


This document provides methods and materials related to managing weight, supporting appetite control, and controlling cravings associated with smoking reduction or cessation regimens and/or nicotine reduction or cessation regimens. For example, compositions comprising an agent to support acetylcholine and an agent to support one or more biogenic amines, and methods for using such compositions for craving and appetite control are provided. Methods and materials to reduce cravings associated with the reduction or cessation of the use of chemical substances (e.g., drugs of abuse, including opioids, cocaine, methamphetamine, cannabis, alcohol), and to reduce cravings associated with addictive and/or compulsive behaviors (e.g., gambling, sex, and repetitive behaviors) are also provided.

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