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Thomaz Fleury Curado, Kenneth Fishbein, Huy Pho, Michael Brennick, Olga Dergacheva, Luiz U Sennes, Luu V Pham, Ellen E Ladenheim, Richard Spencer, David Mendelowitz, Alan R Schwartz, Vsevolod Y Polotsky
Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons...
March 10, 2017: Scientific Reports
Wan Wang, Weisong Duan, Ying Wang, Di Wen, Yakun Liu, Zhongyao Li, Haojie Hu, Hongying Cui, Can Cui, Huiqian Lin, Chunyan Li
Amyotrophic lateral sclerosis (ALS) is an adult-onset, irreversible neurodegenerative disease that leads to progressive paralysis and inevitable death 3-5 years after diagnosis. The mechanisms underlying this process remain unknown, but new evidence indicates that accumulating levels of D-serine result from the downregulation of D-amino acid oxidase (DAO) and that this is a novel mechanism that leads to motoneuronal death in ALS via N-methyl-D-aspartate receptor-mediated cell toxicity. Here, we explored a new therapeutic approach to ALS by overexpressing DAO in the lumbar region of the mouse spinal cord using a single stranded adeno-associated virus serotype 9 (ssAAV9) vector...
December 26, 2016: Neurochemical Research
Valentina Cappello, Laura Marchetti, Paola Parlanti, Silvia Landi, Ilaria Tonazzini, Marco Cecchini, Vincenzo Piazza, Mauro Gemmi
Krabbe disease (KD) is a neurodegenerative disorder caused by the lack of β- galactosylceramidase enzymatic activity and by widespread accumulation of the cytotoxic galactosyl-sphingosine in neuronal, myelinating and endothelial cells. Despite the wide use of Twitcher mice as experimental model for KD, the ultrastructure of this model is partial and mainly addressing peripheral nerves. More details are requested to elucidate the basis of the motor defects, which are the first to appear during KD onset. Here we use transmission electron microscopy (TEM) to focus on the alterations produced by KD in the lower motor system at postnatal day 15 (P15), a nearly asymptomatic stage, and in the juvenile P30 mouse...
December 2016: Scientific Reports
Federica Marelli, Silvia Carra, Giuditta Rurale, Franco Cotelli, Luca Persani
BACKGROUND: Heterozygous mutations in the thyroid hormone receptor alpha (THRA) gene cause resistance to thyroid hormone alpha (RTHα), a disease characterized by variable manifestations reminiscent of untreated congenital hypothyroidism but a raised triiodothyronine/thyroxine ratio and normal thyrotropin levels. It was recently described that zebrafish embryos expressing a dominant negative (DN) form of thraa recapitulate the key features of RTHα, and that zebrafish and human receptors are functionally interchangeable...
February 2017: Thyroid: Official Journal of the American Thyroid Association
Adam J Rossano, Akira Kato, Karyl I Minard, Michael F Romero, Gregory T Macleod
KEY POINTS: Intracellular pH regulation is vital to neurons as nerve activity produces large and rapid acid loads in presynaptic terminals. Rapid clearance of acid loads is necessary to maintain control of neurotransmission, but neuronal acid clearance mechanisms remain poorly understood. Glutamate is loaded into synaptic vesicles via the vesicular glutamate transporter (VGLUT), a mechanism conserved across phyla, and this study reports a previously unknown role for VGLUT as an acid-extruding protein when deposited in the plasmamembrane during exocytosis...
February 1, 2017: Journal of Physiology
Eileen Rodriguez-Tapia, Alberto Perez-Medina, Xiaochun Bian, James J Galligan
Enteric inhibitory motoneurons use nitric oxide and a purine neurotransmitter to relax gastrointestinal smooth muscle. Enteric P/Q-type Ca(2+) channels contribute to excitatory neuromuscular transmission; their contribution to inhibitory transmission is less clear. We used the colon from tottering mice (tg/tg, loss of function mutation in the α1A pore-forming subunit of P/Q-type Ca(2+) channels) to test the hypothesis that P/Q-type Ca(2+) channels contribute to inhibitory neuromuscular transmission and colonic propulsive motility...
October 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Suming Shi, Lei Xu, Jianfeng Li, Yuechen Han, Haibo Wang
Facial nucleus motoneurons innervating the facial expressive muscles are involved in a wide range of motor activities, however, the types of movement related neurons and their electrophysiological transformation after peripheral facial nerve injury haven't been revealed. This study was designed to elucidate the types of facial nucleus motoneurons and their alterations of discharge parameters following peripheral facial nerve injury in vivo. Here we set up a rat model by implanting electrode arrays into the brainstem and recorded the electrophysiological signals of facial nucleus neurons in the intact rats for 5 days, then transected the trunk of facial nerve (TF), and continued the record for 4 weeks...
August 26, 2016: Neuroscience Letters
Izhak David, Philip Holmes, Amir Ayali
Cockroaches are rapid and stable runners whose gaits emerge from the intricate, and not fully resolved, interplay between endogenous oscillatory pattern-generating networks and sensory feedback that shapes their rhythmic output. Here we studied the endogenous motor output of a brainless, deafferented preparation. We monitored the pilocarpine-induced rhythmic activity of levator and depressor motor neurons in the mesothoracic and metathoracic segments in order to reveal the oscillatory networks' architecture and interactions...
September 15, 2016: Biology Open
Julien Colomb, Björn Brembs
Tethering a fly for stationary flight allows for exquisite control of its sensory input, such as visual or olfactory stimuli or a punishing infrared laser beam. A torque meter measures the turning attempts of the tethered fly around its vertical body axis. By punishing, say, left turning attempts (in a homogeneous environment), one can train a fly to restrict its behaviour to right turning attempts. It was recently discovered that this form of operant conditioning (called operant self-learning), may constitute a form of motor learning in Drosophila...
2016: PeerJ
Gerburg Keilhoff, Benjamin Lucas, Katja Uhde, Hisham Fansa
The present study was conducted to investigate the effects of minocycline on the expression of selected transcriptional and translational profiles in the rat spinal cord following sciatic nerve (SNR) transection and microsurgical coaptation. The mRNA and protein expression levels of B cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, major histocompatibility complex I (MHC I), tumor necrosis factor-α (TNF-α), activating transcription factor 3 (ATF3), vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP9), and growth associated protein-43 (GAP-43) were monitored in the rat lumbar spinal cord following microsurgical reconstruction of the sciatic nerves and minocycline treatment...
May 2016: Experimental and Therapeutic Medicine
Kimberly Johnson, Jessica Barragan, Sarah Bashiruddin, Cody J Smith, Chelsea Tyrrell, Michael J Parsons, Rosemarie Doris, Sarah Kucenas, Gerald B Downes, Carla M Velez, Caitlin Schneider, Catalina Sakai, Narendra Pathak, Katrina Anderson, Rachael Stein, Stephen H Devoto, Jeff S Mumm, Michael J F Barresi
Radial glial cells are presumptive neural stem cells (NSCs) in the developing nervous system. The direct requirement of radial glia for the generation of a diverse array of neuronal and glial subtypes, however, has not been tested. We employed two novel transgenic zebrafish lines and endogenous markers of NSCs and radial glia to show for the first time that radial glia are essential for neurogenesis during development. By using the gfap promoter to drive expression of nuclear localized mCherry we discerned two distinct radial glial-derived cell types: a major nestin+/Sox2+ subtype with strong gfap promoter activity and a minor Sox2+ subtype lacking this activity...
July 2016: Glia
Lorena Benedetti, Anna Ghilardi, Elsa Rottoli, Marcella De Maglie, Laura Prosperi, Carla Perego, Mirko Baruscotti, Annalisa Bucchi, Luca Del Giacco, Maura Francolini
The pathogenic role of SOD1 mutations in amyotrophic lateral sclerosis (ALS) was investigated using a zebrafish disease model stably expressing the ALS-linked G93R mutation. In addition to the main pathological features of ALS shown by adult fish, we found remarkably precocious alterations in the development of motor nerve circuitry and embryo behavior, and suggest that these alterations are prompted by interneuron and motor neuron hyperexcitability triggered by anomalies in the persistent pacemaker sodium current INaP...
April 15, 2016: Scientific Reports
Hojjat Radinmehr, Noureddin Nakhostin Ansari, Soofia Naghdi, Gholamreza Olyaei, Azadeh Tabatabaei
Purpose To examine the effects of radial extracorporeal shockwave therapy (rESWT) on plantarflexor spasticity after stroke. Method Twelve patients with stroke were randomly included for this prospective, single-blind clinical trial. Patients received one rESWT session (0.340 mJ/mm(2), 2000 shots) on plantarflexor muscle. The Modified Modified Ashworth Scale (MMAS), H-reflex tests, ankle range of motion (ROM), passive plantarflexor torque (PPFT) and timed up and go test (TUG) were measured at baseline (T0), immediately after treatment (T1) and one hour after the end of the treatment (T2)...
March 2017: Disability and Rehabilitation
Vivek Mahadevan, Melanie A Woodin
KCC2 is the central regulator of neuronal Cl(-) homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity...
May 15, 2016: Journal of Physiology
A A Chelnokov, R M Gorodnichev
Age peculiarities of spinal inhibition in males in the relative muscular rest condition were studied. The main stages of development and formation processes of spinal inhibition in males, and set periods of weakening and increasing during ontogeny. It's shown, that the development and formation of different types of spinal inhibition in the period from 9 to 18 years there heterochronically and definitive level of their development are on a different age: presynaptic inhibition of heteronymous Ia afferent and reciprocal inhibition homonymous α-motoreurons in the age of 9-12 years, recurrent inhibition of heteronymous α-motorneurons--17-18 years, and nonreciprocal inhibition of heteronymous and homonymous α-motorneurons--14-15 years...
November 2015: Fiziologiia Cheloveka
Lorenzo Garavaglia, Erika Molteni, Elena Beretta, Elena Vassena, Sandra Strazzer, Simone Pittaccio
Upper motoreuron lesions (UML) affects people of all ages and conditions and is a major cause of disability in the young. Whereas active exercise is recognised as paramount to restore the lost motor functions, passive mobilisation of the affected limbs is regarded as a means to safeguard muscular tissue properties during a period of disuse and lack of voluntary control, which often characterises the acute and sub-acute phases. The purpose of the present work is to study the cortical reactivity in UML patients who are treated for two weeks with a robotic passive ankle mobiliser, and the clinical effects of this treatment...
2015: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
Stefan Kwiatkowski, Vitaliy M Sviripa, Zhaiyi Zhang, Alison E Wendlandt, Claudia Höbartner, David S Watt, Stefan Stamm
Phosphorylation and dephosphorylation of splicing factors play a key role in pre-mRNA splicing events, and cantharidin and norcantharidin analogs inhibit protein phosphatase-1 (PP1) and change alternative pre-mRNA splicing. Targeted inhibitors capable of selectively inhibiting PP-1 could promote exon 7 inclusion in the survival-of-motorneuron-2 gene (SMN2) and shift the proportion of SMN2 protein from a dysfunctional to a functional form. As a prelude to the development of norcantharidin-tethered oligonucleotide inhibitors, the synthesis a norcantharidin-tethered guanosine was developed in which a suitable tether prevented the undesired cyclization of norcantharidin monoamides to imides and possessed a secondary amine terminus suited to the synthesis of oligonucleotides analogs...
February 1, 2016: Bioorganic & Medicinal Chemistry Letters
Alain de Bruin, Peter W A Cornelissen, Bettina C Kirchmaier, Michal Mokry, Elhadi Iich, Ella Nirmala, Kuo-Hsuan Liang, Anna M D Végh, Koen T Scholman, Marian J Groot Koerkamp, Frank C Holstege, Edwin Cuppen, Stefan Schulte-Merker, Walbert J Bakker
In this study, we explored the existence of a transcriptional network co-regulated by E2F7 and HIF1α, as we show that expression of E2F7, like HIF1α, is induced in hypoxia, and because of the previously reported ability of E2F7 to interact with HIF1α. Our genome-wide analysis uncovers a transcriptional network that is directly controlled by HIF1α and E2F7, and demonstrates both stimulatory and repressive functions of the HIF1α -E2F7 complex. Among this network we reveal Neuropilin 1 (NRP1) as a HIF1α-E2F7 repressed gene...
May 5, 2016: Nucleic Acids Research
Julius A Steinbeck, Manoj K Jaiswal, Elizabeth L Calder, Sarah Kishinevsky, Andreas Weishaupt, Klaus V Toyka, Peter A Goldstein, Lorenz Studer
Capturing the full potential of human pluripotent stem cell (PSC)-derived neurons in disease modeling and regenerative medicine requires analysis in complex functional systems. Here we establish optogenetic control in human PSC-derived spinal motorneurons and show that co-culture of these cells with human myoblast-derived skeletal muscle builds a functional all-human neuromuscular junction that can be triggered to twitch upon light stimulation. To model neuromuscular disease we incubated these co-cultures with IgG from myasthenia gravis patients and active complement...
January 7, 2016: Cell Stem Cell
Christopher A Hinckley, William A Alaynick, Benjamin W Gallarda, Marito Hayashi, Kathryn L Hilde, Shawn P Driscoll, Joseph D Dekker, Haley O Tucker, Tatyana O Sharpee, Samuel L Pfaff
The coordination of multi-muscle movements originates in the circuitry that regulates the firing patterns of spinal motorneurons. Sensory neurons rely on the musculotopic organization of motorneurons to establish orderly connections, prompting us to examine whether the intraspinal circuitry that coordinates motor activity likewise uses cell position as an internal wiring reference. We generated a motorneuron-specific GCaMP6f mouse line and employed two-photon imaging to monitor the activity of lumbar motorneurons...
September 2, 2015: Neuron
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