المؤلفون: Lidong Liu, Tak Pan Wong, Mario F Pozza, Kurt Lingenhoehl, Yushan Wang, Morgan Sheng, Yves P Auberson, Yu Tian Wang

المساهمون: The Pennsylvania State University CiteSeerX Archives

المصدر: http://science.sciencemag.org/content/sci/304/5673/1021.full.pdfTest.

الوصف: Activation of N-methyl-D-aspartate subtype glutamate receptors (NMDARs) is required for long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular substrates of learning and memory. However, little is known about how activation of NMDARs leads to these two opposing forms of synaptic plasticity. Using hippocampal slice preparations, we showed that selectively blocking NMDARs that contain the NR2B subunit abolishes the induction of LTD but not LTP. In contrast, preferential inhibition of NR2A-containing NMDARs prevents the induction of LTP without affecting LTD production. These results demonstrate that distinct NMDAR subunits are critical factors that determine the polarity of synaptic plasticity. The molecular mechanisms underlying activity-dependent modification of synaptic strength have been under intensive investigation because of their fundamental importance in brain function and dysfunction (1, 2). Homosynaptic long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission mediated by ␣-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid subtype glutamate receptors (AMPARs) at Schaffer collateral-CA1 synapses of the hippocampus are by far the best-characterized cellular models of synaptic plasticity. Both LTP and LTD require N-methyl-D-aspartate subtype glutamate receptor (NMDAR) activation (1, 3). However, the detailed mechanisms by which the activation of the same class of receptor can produce two opposing forms of synaptic modification remain unclear. A long-held belief has been that the degree of NMDAR activation, and hence the level of postsynaptic calcium elevation during the induction period, dictates the direction of NMDAR-dependent synaptic modification. The strongest evidence for this hypothesis comes from the conversion of LTP to LTD by a partial blockade of NMDARs with low concentrations of the NMDAR antagonist D,L-2-amino-5-phosphophonovaleric acid (APV) (4, 5 ). NMDARs are assembled ...

وصف الملف: application/pdf

العلاقة: http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.1035.9660Test; http://science.sciencemag.org/content/sci/304/5673/1021.full.pdfTest

الإتاحة: http://science.sciencemag.org/content/sci/304/5673/1021.full.pdfTest

المؤلفون: Doncho P. Uzunov, Kevin H. McAllister, Frederique Chaperon, Markus Fendt, Stefan Imobersteg, David Orain, Kurt Lingenhöhl, Hugo Bürki

المصدر: Psychopharmacology. 206:291-301

مصطلحات موضوعية: Male, medicine.medical_specialty, Time Factors, Conditioning, Classical, Central nervous system, Neuropeptide, Peptide hormone, Arginine, Fear-potentiated startle, Amygdala, Oligodeoxyribonucleotides, Antisense, Mice, Internal medicine, mental disorders, medicine, Animals, Neuropeptide Y, Freezing Reaction, Cataleptic, Receptor, Mice, Knockout, Pharmacology, Analysis of Variance, Electroshock, Dose-Response Relationship, Drug, Antagonist, Fear, Neuropeptide Y receptor, Peptide Fragments, humanities, Receptors, Neuropeptide Y, Mice, Inbred C57BL, Endocrinology, medicine.anatomical_structure, Gene Expression Regulation, nervous system, Mice, Inbred DBA, Models, Animal, Psychology

الوصف: Neuropeptide Y (NPY) and its receptors are densely localized in brain regions involved in the mediation and modulation of fear, including the amygdala. Several studies showed that central NPY is involved in the modulation of fear and anxiety. In the present study, we investigated (1) whether intra-amygdala injections of NPY affect the expression of conditioned fear and (2) whether NPY Y1 receptors (Y1R) mediates the effects of these intra-amygdaloid NPY injections. Intra-amygdala NPY injections robustly decreased the expression of conditioned fear measured by conditioned freezing and fear-potentiated startle. These NPY effects were not mimicked by intra-amygdala injections of the Y1R agonists Y-28 or Y-36, and co-infusion of the Y1R antagonist BIBO 3304 did not block the NPY effects. Furthermore, we tested Y1R-deficient mice in conditioned freezing and found no differences between wild type and mutant littermates. Finally, we injected NPY into the amygdala of Y1R-deficient mice. Y1R deficiency had no effect on the fear-reducing effects of intra-amygdala NPY. These data show an important role of the transmitter NPY within the amygdala for the expression of conditioned fear. Y1R do not appear to be involved in the mediation of the observed intra-amygdala NPY effects suggesting that these effects are mediated via other NPY receptors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b834b174233d79eed435d36de9b848fcTest
https://doi.org/10.1007/s00213-009-1610-8Test

المؤلفون: Will P.J.M Spooren, Andrzej Pilc, Ivo Vranesic, Natacha Stoehr, Peter J. Flor, Kurt Lingenhöhl, Annick Vassout, Adriana Pagano, Fabrizio Gasparini, Rainer Kuhn, Conrad Gentsch

المصدر: Amino Acids. 23:207-211

مصطلحات موضوعية: Binding Sites, Allosteric modulator, Pyridines, Metabotropic glutamate receptor 5, Chemistry, Receptor, Metabotropic Glutamate 5, Metabotropic glutamate receptor 4, Organic Chemistry, Clinical Biochemistry, Metabotropic glutamate receptor 7, Brain, Pain, Class C GPCR, Anxiety, Pharmacology, Ligands, Receptors, Metabotropic Glutamate, Biochemistry, Anti-Anxiety Agents, Metabotropic glutamate receptor, Animals, Metabotropic glutamate receptor 1, Metabotropic glutamate receptor 2, Excitatory Amino Acid Antagonists

الوصف: There is a need to identify subtype-specific ligands for mGlu receptors to elucidate the potential of these receptors for the treatment of nervous system disorders. To date, most mGlu receptor antagonists are amino acid-like compounds acting as competitive antagonists at the glutamate binding site located in the large extracellular N-terminal domain. We have characterized novel subtype-selective mGlu(5) receptor antagonists which are structurally unrelated to competitive mGlu receptor ligands. Using a series of chimeric receptors and point mutations we demonstrate that these antagonists act as inverse agonists with a novel allosteric binding site in the seven-transmembrane domain. Recent studies in animal models implicate mGlu(5) receptors as a potentially important therapeutic target particularly for the treatment of pain and anxiety.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::527b87686efb44e1c71d60e7bb3f6de3Test
https://doi.org/10.1007/s00726-001-0130-6Test

المؤلفون: Brigitte Schulz, Markus Fendt, Michael Koch, Fabrizio Gasparini, Rainer Kuhn, Kurt Lingenhöhl

المصدر: Neuropharmacology. 41:1-7

مصطلحات موضوعية: Male, Reflex, Startle, Pyridines, medicine.drug_class, Pharmacology, Receptors, Metabotropic Glutamate, Anxiolytic, Fear-potentiated startle, Rats, Sprague-Dawley, Cellular and Molecular Neuroscience, Memory, Conditioning, Psychological, mental disorders, Moro reflex, medicine, Animals, Learning, Fear conditioning, Habituation, Psychophysiologic, Electroshock, Metabotropic glutamate receptor 5, Fear, 2-Methyl-6-(phenylethynyl)pyridine, Rats, Metabotropic receptor, Acoustic Stimulation, Metabotropic glutamate receptor, Psychology, Excitatory Amino Acid Antagonists, Neuroscience

الوصف: Glutamate receptors play an essential role in fear-related learning and memory. The present study was designed to assess the role of the group I metabotropic glutamate receptor (mGluR) subtype 5 in the acquisition and retrieval of conditioned fear in rats. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was applied systemically (0.0, 0.3, 3.0, 30.0 mg/kg per os) 60 min before the acquisition training and before the expression of conditioned fear, respectively, in the fear-potentiated startle paradigm. MPEP dose-dependently blocked the acquisition of fear. This effect was not due to state-dependent learning. MPEP also prevented the expression of fear at a dose of 30.0 mg/kg. As a positive control for these effects, we showed that the benzodiazepine anxiolytic compound diazepam (1.25 mg/kg intraperitoneally) also blocked acquisition and expression of fear potentiated startle. MPEP did not affect the baseline startle magnitude, short-term habituation of startle, sensitisation of startle by footshocks or prepulse inhibition of startle. These data indicate a crucial role for mGluR5 in the regulation of fear conditioning. In the highest dose MPEP might exert anxiolytic properties.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be4c985dd94c0b4c1525a0fd24cac80fTest
https://doi.org/10.1016/s0028-3908Test(01)00036-3

المؤلفون: Frank Narz, Peter R. Allegrini, Christoph G. Goemans, Kurt Lingenhöhl, Hartmut Berns, Daniela Bartsch, Bastian Hengerer, Erwin F. Wagner, Rolf Heumann, Rigobert H. Kamdem, Thomas Arendt, Karl Schellander, Peter C. Waldmeier, Kirstin Obst-Pernberg, Petra Wahle

المصدر: The Journal of Cell Biology

مصطلحات موضوعية: 1-Methyl-4-phenylpyridinium, Cell Count, Mice, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, Neuropeptide Y, Phosphorylation, Cells, Cultured, Motor Neurons, biology, Brain, Axotomy, Neurodegenerative Diseases, protection, Cell biology, Substantia Nigra, Neuroprotective Agents, Proto-Oncogene Proteins c-bcl-2, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Original Article, Mitogen-Activated Protein Kinases, Signal transduction, Oxidopamine, Signal Transduction, Neurotrophin, Tyrosine 3-Monooxygenase, Mice, Transgenic, Protein Serine-Threonine Kinases, Neuroprotection, Choline O-Acetyltransferase, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins, Animals, RNA, Messenger, Protein kinase B, mouse, Cell Size, transgenic, Tyrosine hydroxylase, Hypertrophy, Cell Biology, Molecular biology, neuron, Enzyme Activation, nervous system, Ras Signaling Pathway, chemistry, Mutation, biology.protein, Proto-Oncogene Proteins c-akt, Ras

الوصف: Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-XL. Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1a7f9ec6f11c12860354c73aad119068Test
https://doi.org/10.1083/jcb.151.7.1537Test

المؤلفون: Kurt Lingenhöhl, Serge Bischoff, Kaspar Zimmermann, Mario F. Pozza

المصدر: Progress in Neuro-Psychopharmacology and Biological Psychiatry. 24:647-670

مصطلحات موضوعية: Pharmacology, Voltage clamp, Kainate receptor, Strychnine, AMPA receptor, Biology, chemistry.chemical_compound, nervous system, Biochemistry, chemistry, In vivo, Glycine, Biophysics, NMDA receptor, Glycine receptor, Biological Psychiatry

الوصف: 1. 1. Electrophysiological experiments were performed in vitro and vivo . Voltage clamp recordings were done in Xenopus oocytes. Extracellular recordings were done in vitro in the neocortical slice and in the CA1 region of the hippocampal slice and vivo in the CA1 region of the hippocampus of the anaesthetized rat. 2. 2. In oocytes expressing either the human NMDAR1 a /2 a or 1 a /2 b subunit combinations, CGP68730A [sodium (−)-9-bromo-2,3,6,7-tetrahydro-5,6-dioxo-5H-pyrazino[1,2,3-de]-1,4-benzothiazine-3-acetic acid] antagonized L-glutamate / glycine induced currents with calculated IC 50 S of 20.5 and 81.6 nM, respectively. 3. 3. In vitro , CGP68730A was tested on NMDA induced depolarizations in the neocortical slice preparation and on epileptiform activity in hippocampal slices bathed in Mg 2+ -free-medium, which is known to be NMDA mediated. In both in vitro models CGP68730A exhibited antagonistic effects on the NMDA receptor mediated responses. 4. 4. In vivo CGP68730A was tested on NMDA induced excitations in the CA1 region. CGP68730A abolished NMDA induced excitations when applied microiontophoretically. However, only weak effects on NMDA induced excitation were observed after systemic administration at 100 mg/kg i.V. These results indicate that CGP68730A has poor central nervous system bioavailability. 5. 5. In oocytes, an increase in the glycine concentration from the EC 80 to the EC 95–99 shifted the inhibition curves for CGP68730A to the right. Furthermore, in neocortical slices and in anaesthetized rats CGP68730A inhibited NMDA mediated depolarizations, and this effect could be reversed by the addition of the glycine mimetic D-serine. This indicates that these effects of CGP68730A are mediated by an action on the strychnine-insensitive glycine site. 6. 6. Selectivity tests in oocytes and in the neocortical slice preparation, using NMDA, kainate and AMPA showed that CGP68730A was selective in antagonizing NMDA receptor mediated responses. In oocytes, the compound was about 1000 times less potent on the rat GluR3 and the human GluR6 receptors than on the human NMDAR1 a /2 a subunit combination. In the neocortical slice preparation CGP68730A had no effects on AMPA or kainate induced depolarizations at concentrations of 3 and 10 μM. At 30 μM CGP68730A reduced the effects of each of the three agonists tested. 7. 7. Thus, CGP68730A seems to be a selective antagonist at the strychnine-insensitive glycine coagonist site of the NMDA receptor. However, the compound showed no obvious central NMDA antagonistic effects following intravenous application.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::fc1728172e77abeb445a5470e5f4f8f3Test
https://doi.org/10.1016/s0278-5846Test(00)00099-3

المؤلفون: Kurt Lingenhöhl, Mario F. Pozza

المصدر: Neuropharmacology. 37:729-737

مصطلحات موضوعية: Male, N-Methylaspartate, Neocortex, Kainate receptor, AMPA receptor, Biology, Pharmacology, Hippocampus, Receptors, N-Methyl-D-Aspartate, Neuroprotection, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Quinoxalines, Animals, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Glycine receptor, Licostinel, Glutamate receptor, Strychnine, Acetylcholine, Rats, Electrophysiology, nervous system, chemistry, NMDA receptor, Excitatory Amino Acid Antagonists

الوصف: Electrophysiological experiments were performed in vitro and in vivo to characterize the inhibitory effects of 6,7-dichloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (ACEA 1021; licostinel) on rat brain glutamate receptors. In vitro, ACEA 1021 was tested on N-methyl-D-aspartate (NMDA)-induced depolarizations in the neocortical slice preparation and on epileptiform activity in Mg2+-free hippocampal slices, which is known to be NMDA receptor mediated. In both in vitro models, ACEA 1021 exhibited antagonistic effects on the NMDA receptor-mediated responses. Selectivity tests in the neocortical slice preparation, using NMDA, kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) showed that 10 microM ACEA 1021 reduced NMDA and kainate responses to 27.9 and 79.9% of the control value, respectively, whereas responses to AMPA were increased by 2.4% above the control value, thus showing that at this concentration ACEA 1021 acts preferentially at NMDA receptors. However, at 30 microM, all the NMDA-, AMPA- and kainate-induced responses were reduced. In vivo, ACEA 1021 was tested on NMDA-induced excitation in the CA1 region. After systemic administration of ACEA 1021, central effects were observed at 10 mg/kg i.v. in the CA1 region. These results indicate that ACEA 1021 is centrally active and inhibits NMDA receptor-mediated responses. Interestingly, selectivity tests in the CA1 region did not show clear differences in the action of ACEA 1021 on NMDA- and AMPA-induced excitations. Furthermore, ACh-induced excitations were also reduced. Thus, at low concentrations, ACEA 1021 seems to be a selective antagonist at the strychnine-insensitive glycine site of the NMDA receptor. However, at 30 microM in vitro and at 10 mg/kg in vivo, non-NMDA receptor-mediated actions of ACEA 1021 are observed. Our results suggest that these additional effects of ACEA 1021 may contribute to its anticonvulsive properties in mice as well as to its neuroprotective properties in animal models of cerebral ischemia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9742a6d9722bff5dafd1d0102e1c7429Test
https://doi.org/10.1016/s0028-3908Test(98)00062-8

المؤلفون: Eckhard Friauf, Kurt Lingenhöhl

المصدر: Scopus-Elsevier

مصطلحات موضوعية: Reflex, Startle, Startle response, Auditory Pathways, Biology, Reticular formation, Synaptic Transmission, Neurons, Efferent, Evoked Potentials, Auditory, Brain Stem, medicine, Animals, Neurons, Afferent, Habituation, Psychophysiologic, Neurons, medicine.diagnostic_test, Reticular Formation, General Neuroscience, Lateral lemniscus, Articles, Amygdala, Electric Stimulation, Rats, Anterograde tracing, Electrophysiology, Acoustic Stimulation, nervous system, Superior olivary complex, Caudal pontine reticular nucleus, Auditory Perception, Auditory nuclei, Female, Neuroscience, Brain Stem

الوصف: The mammalian acoustic startle response (ASR) is a relatively simple motor response that can be elicited by sudden and loud acoustic stimuli. The ASR shows several forms of plasticity, such as habituation, sensitization, and prepulse inhibition, thereby making it an interesting model for studying the underlying neuronal mechanisms. Among the neurons that compose the elementary startle circuit are giant neurons in the caudal pontine reticular nucleus (PnC), which may be good candidates for analyzing the neuronal basis of mammalian behavior. In a first step of this study, we employed retrograde and anterograde tracing techniques to identify the possible sources of input and the efferent targets of these neurons. In a second step, we performed intracellular recordings in vivo, followed by subsequent injections of HRP for morphological identification, thereby investigating whether characteristic features of the ASR are reflected by physiological properties of giant PnC neurons. Our observations demonstrate convergent, bilateral input from several auditory brainstem nuclei to the PnC, predominantly originating from neurons in the cochlear nuclear complex and the superior olivary complex. Almost no input neurons were found in the nuclei of the lateral lemniscus. As the relatively long neuronal response latencies in several of these auditory nuclei appear to be incompatible with the primary ASR, we conclude that neurons in the cochlear root nuclei most likely provide the auditory input to PnC neurons that is required to elicit the ASR. The giant PnC neurons have a remarkable number of physiological features supporting the hypothesis that they may be a neural correlate of the ASR: (1) they receive short- latency auditory input, (2) they have high firing thresholds and broad frequency tuning, (3) they are sensitive to changes in stimulus rise time and to paired-pulse stimulation, (4) repetitive acoustic stimulation results in habituation of their response, and (5) amygdaloid activity enhances their response to acoustic stimuli. Anterograde tracing showed that most giant PnC neurons are reticulospinal cells. Axon collaterals and terminal arbors were found in the reticular formation as well as in cranial and spinal motoneuron pools. The results of this study indicate that giant PnC neurons form a sensorimotor interface between the cochlear nuclear complex and cranial and spinal motoneurons. This neuronal pathway implies that the elementary acoustic startle circuit is composed of only three central relay stations and thus appears to be organized more simply than assumed in the past.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::972878f8432c9c8fab017222a8d91cadTest
https://doi.org/10.1523/jneurosci.14-03-01176.1994Test

المؤلفون: Ivo Vranesic, Kyla Omilusik, Hanspeter Müller, Kurt Lingenhöhl, Christine Stierlin, Peter J. Flor, Fabrizio Gasparini, Rainer Kuhn, Micheline Heinrich, Natacha Stoehr, Veronica C. Munk, Werner Inderbitzin, Hendrik Andres

المصدر: Bioorganic & Medicinal Chemistry Letters. 12:407-409

مصطلحات موضوعية: Pyridines, Receptor, Metabotropic Glutamate 5, Clinical Biochemistry, Pharmaceutical Science, Ether, Ligands, Receptors, Metabotropic Glutamate, Binding, Competitive, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Drug Discovery, Radioligand, Humans, Molecular Biology, Binding Sites, Chemistry, Organic Chemistry, Biological activity, Subtype selective, Recombinant Proteins, In vitro, Kinetics, Metabotropic receptor, Metabotropic glutamate receptor, Molecular Medicine, Radiopharmaceuticals

الوصف: The synthesis of a new potent, subtype-selective radioligand [3H]-M-MPEP (2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine) and its in vitro pharmacological characteristics are described. ©2002 Elsevier Science Ltd. All rights reserved.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ee5d31f37f29df72ba78b1c869ec86fcTest
https://doi.org/10.1016/s0960-894xTest(01)00767-3

المؤلفون: Guido Filacchioni, Kurt Lingenhöhl, Ombretta Lenzi, Daniela Poli, Flavia Varano, Daniela Catarzi, Silvio Ofner, Vittoria Colotta

المصدر: Università degli studi di Firenze-IRIS

مصطلحات موضوعية: Stereochemistry, medicine.medical_treatment, Ligand binding assay, General Chemistry, General Medicine, AMPA receptor, Rats, chemistry.chemical_compound, Mice, Quinoxaline, Anticonvulsant, chemistry, Competitive antagonist, Seizures, Quinoxalines, Drug Discovery, medicine, Oocytes, Quinazolines, Homomeric, Animals, Anticonvulsants, Receptors, AMPA, Receptor, AMPA Receptor Antagonists

الوصف: In the present study, some selected, previously reported 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) and 3-hydroxy-quinazoline-2,4-diones (QZs), were evaluated for their affinity at the (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid (AMPA) receptor in the [(3)H]-6-cyano-7-nitroquinoxaline-2,3-dione ([(3)H]-CNQX) binding assay. Electrophysiological experiments were performed in oocytes expressing rat homomeric GluR3 subunits in order to assess the pharmacological profile of the tested compounds. The binding data, together with those regarding the functional activity, confirmed that most of the TQXs and QZs reported herein are potent AMPA receptor antagonists. When tested for their ability to prevent sound-induced seizures in DBA/2 mice, some of these derivatives showed anticonvulsant properties.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b7e9e15a80850fac3b062cd7d0316c62Test
https://pubmed.ncbi.nlm.nih.gov/20606335Test