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Trushar R Patel, Tabot M D Besong, Markus Meier, Kevin McEleney, Stephen E Harding, Donald J Winzor, Jörg Stetefeld
The major challenges in biophysical characterization of human protein-carbohydrate interactions are obtaining monodispersed preparations of human proteins that are often post-translationally modified and lack of detection of carbohydrates by traditional detection systems. Light scattering (dynamic and static) techniques offer detection of biomolecules and their complexes based on their size and shape, and do not rely on chromophore groups (such as aromatic amino acid sidechains). In this study, we utilized dynamic light scattering, analytical ultracentrifugation and small-angle X-ray scattering techniques to investigate the solution properties of a complex resulting from the interaction between a 15 kDa heparin preparation and miniagrin, a miniaturized version of agrin...
March 12, 2018: European Biophysics Journal: EBJ
Ryo Ueta, Yuji Yamanashi
The neuromuscular junction(NMJ)is the synapse between a motor neuron and the skeletal muscle that is essential for muscle contraction. Impairments at the NMJ lead to neuromuscular-transmission pathologies characterized by fatigable muscle weakness. Muscle-specific receptor tyrosine kinase MuSK plays key roles in NMJ formation. Over the past decade, studies examining the NMJ formation signals have identified molecules involved in the signaling pathways and have promoted a better understanding of characteristic molecular mechanisms for MuSK activation...
2018: Clinical Calcium
Moriah E Katt, Raleigh M Linville, Lakyn N Mayo, Zinnia S Xu, Peter C Searson
BACKGROUND: Transwell-based models of the blood-brain barrier (BBB) incorporating monolayers of human brain microvascular endothelial cells (dhBMECs) derived from induced pluripotent stem cells show many of the key features of the BBB, including expression of transporters and efflux pumps, expression of tight junction proteins, and physiological values of transendothelial electrical resistance. The fabrication of 3D BBB models using dhBMECs has so far been unsuccessful due to the poor adhesion and survival of these cells on matrix materials commonly used in tissue engineering...
February 20, 2018: Fluids and Barriers of the CNS
Melissa R Wrobel, Harini G Sundararaghavan
Following peripheral nerve injury (PNI), inflammatory cues impede repair. We have previously demonstrated that spinal cord matrix (SCM) proteins and hyaluronic acid (HA) nanofibers mitigate chondroitin sulfate proteoglycan (CSPG) inhibition and promote growth in peripheral neurons. In this study, we evaluated the effects of a characteristic CSPG, Chondroitin sulfate A (CSA), SCM, and HA fibers on macrophages and Schwann Cells (SCs). We hypothesized that our cues would accelerate the macrophages return to rest following classical activation (M1/pro-inflammatory) with lipopolysaccharide (LPS; 1μg/mL) and would accelerate the transformation of SCs from an immature state following injury to a mature/pro-myelinating phenotype...
February 17, 2018: Neuroscience
Emily O'Connor, Vietxuan Phan, Isabell Cordts, George Cairns, Stefan Hettwer, Daniel Cox, Hanns Lochmüller, Andreas Roos
Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by compromised function of the neuromuscular junction, manifesting with fatigable muscle weakness. Mutations in MYO9A were previously identified as causative for CMS but the precise pathomechanism remained to be characterised. Based on the role of MYO9A as an actin-based molecular motor and as a negative regulator of RhoA, we hypothesised that loss of MYO9A may affect the neuronal cytoskeleton, leading to impaired intracellular transport...
February 16, 2018: Human Molecular Genetics
Marina Boido, Elena De Amicis, Valeria Valsecchi, Marco Trevisan, Ugo Ala, Markus A Ruegg, Stefan Hettwer, Alessandro Vercelli
Spinal muscular atrophy (SMA) is a pediatric genetic disease, characterized by motor neuron (MN) death, leading to progressive muscle weakness, respiratory failure, and, in the most severe cases, to death. Abnormalities at the neuromuscular junction (NMJ) have been reported in SMA, including neurofilament (NF) accumulation at presynaptic terminals, immature and smaller than normal endplates, reduced transmitter release, and, finally, muscle denervation. Here we have studied the role of agrin in SMAΔ7 mice, the experimental model of SMAII...
2018: Frontiers in Cellular Neuroscience
Sayan Chakraborty, Wanjin Hong
In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing towards tissue fibrosis and cancer. The transcriptional co-activators YAP/TAZ, better known as the converging effectors of the Hippo pathway, are widely recognized for their new role as nuclear mechanosensors during organ homeostasis and cancer...
February 6, 2018: Cancers
Uwe Rauch, Eva Bengtsson, Isabel Gonçalves, Anna Hultgårdh-Nilsson
The clinical consequences of arterial atherosclerotic lesions depend, apart from their size, on their composition of cellular and extracellular components. While an intact endothelium at the interface of atherosclerotic plaques towards the blood can prevent its erosion, underlying smooth muscle cells within the plaque can reduce the risk of plaque ruptures, due to the deposition of stabilizing extracellular matrix. Basement membranes underlay and support the function of endothelial cells, and embed smooth muscle cells in the media, the source of most smooth muscle cells within atherosclerotic plaques...
February 6, 2018: Histology and Histopathology
Min Yan, Guang-Lin Xing, Wen-Cheng Xiong, Lin Mei
Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4-both critical for neuromuscular junction formation and maintenance-in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti-LRP4 antibodies are causal to MG...
January 28, 2018: Annals of the New York Academy of Sciences
Angela Vincent, Saif Huda, Michelangelo Cao, Hakan Cetin, Inga Koneczny, Pedro Rodriguez-Cruz, Leslie Jacobson, Stuart Viegas, Saiju Jacob, Mark Woodhall, Akiko Nagaishi, Angelina Maniaol, Valentina Damato, M Isabel Leite, Judith Cossins, Richard Webster, Jacqueline Palace, David Beeson
Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10-20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle-specific kinase (MuSK). The use of cell-based assays has extended the repertoire of antibody tests to clustered AChRs, low-density lipoprotein receptor-related protein 4, and agrin...
January 29, 2018: Annals of the New York Academy of Sciences
Diana Erasso, Gabriel C Tender, Qin Li, Jiusheng Yan, Frank Culicchia, Salahadin Abdi, JianGuo Cui
BACKGROUND: Diabetes mellitus affects 9.3% of the US population and increases risks of surgery and complications. Diabetic neuropathic pain (DNP), one of the main consequences of diabetes mellitus, is extremely difficult to treat. Current medications yield limited benefits and/or have severe adverse effects. Therefore, new, effective treatment is needed. METHODS: Streptozotocin at 55 mg/kg was injected intraperitoneally in rats to induce diabetes mellitus. Diabetic rats exhibiting neuropathic pain underwent intrathecal injection of purified agrin proteins at various doses and were then tested for tactile allodynia to evaluate whether DNP was inhibited...
January 23, 2018: Anesthesia and Analgesia
Zhen Xiao, Jing Shu, Feng Zhou, Yong Han
Chronic Obstructive Pulmonary Disease (COPD) is one of the leading cause of morbidity and death worldwide. It is characterized by chronic pulmonary inflammation and obstructed airflow from the lungs. To date, there is no effective treatments for COPD. The activation of Agrin (AGRN) - YAP pathway can promote heart regeneration. Since Agrin can only induce mild cardiomyocyte (CM) proliferation compare to ERBB2 pathway activation, it might exert pleiotropic effects, such as mitigation of innate inflammation, immune response and fibrosis...
December 28, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
Min Yan, Ziyang Liu, Erkang Fei, Wenbing Chen, Xinsheng Lai, Bin Luo, Peng Chen, Hongyang Jing, Jin-Xiu Pan, Michael H Rivner, Wen-Cheng Xiong, Lin Mei
Myasthenia gravis (MG) is an autoimmune disorder ofthe neuromuscular junction (NMJ). Most cases of MG are caused by autoantibodies against the acetylcholine receptor (AChR),muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4). Recent studies have identified anti-agrin antibodies in MG patients lacking these three antibodies (i.e., triple negative MG). Agrin is a basal lamina protein that has two isoforms. Neural agrin (N-agrin) binds to LRP4 to activate MuSK to induce AChR clusters and is thus critical for NMJ formation...
January 12, 2018: Neuroscience
Jordan R Warford, Anna-Claire Lamport, Derek R Clements, Alicia Malone, Barry E Kennedy, Youra Kim, Shashi A Gujar, David W Hoskin, Alexander S Easton
Proteoglycans are promising therapeutic targets in Multiple Sclerosis (MS), because they regulate many aspects of the immune response. This was studied using surfen, an agent that binds both heparan sulphate proteoglycans (HSPGs) and chondroitin sulphate proteoglycans (CSPGs). Initial cell culture work on bone marrow derived macrophages (BMDMs) found that surfen reduced concentrations of the chemokines CCL2, CCL4 and CCL5, with reduced messenger (m)RNA expression for Tumor Necrosis Factor, IL-6, IL-1β and inducible nitric oxide synthase...
January 4, 2018: Acta Neuropathologica Communications
Xing Lv, Cheng Fang, Ruozhe Yin, Bowei Qiao, Runze Shang, Jianlin Wang, Wenjie Song, Yong He, Yong Chen
Evaluating the process and mechanism of fibrogenesis is essential in hepatocellular carcinoma (HCC), especially in hepatocyte transformation and oncogenic signaling. We evaluated the oncogenic role of agrin secreted by platelet-derived growth factor (PDGF)-induced hepatic stellate cell (HSC) in HCC. Cells were co-cultured to investigate the effect of activated HSC on hepatocytes. Liquid chromatography and protein profiling analysis were used to search the distinct proteins secreted in HSC supernatant. Sprague Dawley rats with Diethylnitrosamine (DEN)-induced HCC were used to simulate human liver cancer and sorafenib was administered to investigate its effect on hepatocarcinogenesis...
December 1, 2017: Oncotarget
Zhiguo Li, Minshu Li, Kristofer Wood, Steffan Hettwer, Suraj A Muley, Fu-Dong Shi, Qiang Liu, Shafeeq S Ladha
INTRODUCTION: Agrin is essential for the formation and maintenance of neuromuscular junctions (NMJs). NT-1654 is a C-terminal fragment of mouse neural agrin. In this study, we determined the effects of NT-1654 on the severity of experimental autoimmune myasthenia gravis (EAMG). METHODS: EAMG was induced in female Lewis rats by immunization with the Torpedo acetylcholine receptor (tAChR) and complete Freund's adjuvant (CFA). NT-1654 was dissolved in phosphate-buffered saline (PBS) and injected daily subcutaneously into tAChR immunized rats during the first 10 days after immunization, and then every other day for the following 20 days...
November 28, 2017: Muscle & Nerve
Katsusuke Hata, Yuka Maeno-Hikichi, Norihiro Yumoto, Steven J Burden, Lynn T Landmesser
The neural cell adhesion molecule (NCAM) is expressed both presynaptically and postsynaptically during neuromuscular junction formation. Genetic deletion in mice of all three isoforms (180, 140, and 120 kDa), or just the 180 isoform, suggested that different isoforms played distinct roles in synaptic maturation. Here we characterized in mice of either sex the earliest adhesive contacts between the growth cones of motoneurons and myotubes and their subsequent maturation into functional synapses in cocultures of motoneurons and myotubes, which expressed their normal complement of NCAM isoforms, or were lacking all isoforms either presynaptically or postsynaptically...
January 10, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Taewook Kang, Pia Jensen, Honggang Huang, Gitte Lund Christensen, Nils Billestrup, Martin R Larsen
Normal pancreatic islet β-cells (PBCs) abundantly secrete insulin in response to elevated blood glucose levels, in order to maintain an adequate control of energy balance and glucose homeostasis. However, the molecular mechanisms underlying the insulin secretion are unclear. Improving our understanding of glucose-stimulated insulin secretion (GSIS) mechanisms under normal conditions is a prerequisite for developing better interventions against diabetes. Here, we aimed at identifying novel signaling pathways involved in the initial release of insulin from PBCs after glucose stimulation using quantitative strategies for the assessment of phosphorylated proteins and sialylated N-linked (SA) glycoproteins...
November 7, 2017: Molecular & Cellular Proteomics: MCP
Isabel Illa, Elena Cortés-Vicente, María Ángeles Martínez, Eduard Gallardo
Patients with myasthenia gravis (MG) without antibodies to the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) have been classified as having double-seronegative myasthenia gravis (dSNMG). We used the sera from six dSNMG patients with positive immunohistochemistry assays in a protein array to screen reactivity with 9000 human proteins. We identified cortactin, an intracellular protein that interacts with agrin/MuSK favoring AChR aggregation, as a new antigen in dSNMG. We then designed an in-house enzyme-linked immunosorbent assay as a screening assay and confirmed these results by western blot...
October 25, 2017: Annals of the New York Academy of Sciences
T Gagliano-Jucá, T W Storer, K M Pencina, T G Travison, Z Li, G Huang, S Hettwer, P Dahinden, S Bhasin, S Basaria
In a subset of men, sarcopenia and physical dysfunction occur due to destabilization of the neuromuscular junction (NMJ), which is manifested by elevated serum concentrations of C-terminal agrin fragment (CAF). Testosterone administration improves physical function in some studies; however, its effects on serum circulating CAF concentrations remain unknown. Here we evaluate the effects of testosterone administration on circulating CAF levels in mobility-limited men with low testosterone aged 65 or older participating in the Testosterone in Older Men with Mobility Limitations (TOM) Trial...
September 26, 2017: Andrology
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