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https://www.readbyqxmd.com/read/28340352/human-epistatic-interaction-controls-il7r-splicing-and-increases-multiple-sclerosis-risk
#1
Gaddiel Galarza-Muñoz, Farren B S Briggs, Irina Evsyukova, Geraldine Schott-Lerner, Edward M Kennedy, Tinashe Nyanhete, Liuyang Wang, Laura Bergamaschi, Steven G Widen, Georgia D Tomaras, Dennis C Ko, Shelton S Bradrick, Lisa F Barcellos, Simon G Gregory, Mariano A Garcia-Blanco
Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5' UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk...
March 23, 2017: Cell
https://www.readbyqxmd.com/read/28340145/human-abuse-potential-of-the-new-opioid-analgesic-molecule-nktr-181-compared-with-oxycodone
#2
Lynn Webster, Jack Henningfield, August R Buchhalter, Suresh Siddhanti, Lin Lu, Aleksandrs Odinecs, Carlo J Di Fonzo, Michael A Eldon
Objective.:  Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design.:  This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users. Setting.:  Inpatient clinical research site. Subjects. : Forty-two randomized subjects (73...
March 10, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
https://www.readbyqxmd.com/read/28340102/impact-of-unrestricted-access-to-pregabalin-on-the-use-of-opioids-and-other-cns-active-medications-a-cross-sectional-time-series-analysis
#3
Herman Kwok, Wayne Khuu, Kimberly Fernandes, Diana Martins, Mina Tadrous, Samantha Singh, David N Juurlink, Tara Gomes
Objective. : Access to pregabalin via Ontario's public drug insurance program was expanded to an unrestricted model on April 1, 2013, from a prior authorization model. This study aims to identify the effect of expanded access on the rate of pregabalin use by publicly insured persons and to assess the characteristics of new patients initiating pregabalin following this expanded access. Methods. : We conducted a cross-sectional time series analysis using the linked health administrative records of residents of Ontario, Canada, with public drug coverage who were dispensed a prescription for pregabalin between April 1, 2006, and December 31, 2014...
March 6, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
https://www.readbyqxmd.com/read/28338622/phosphodiesterase-inhibitors-as-a-therapeutic-approach-to-neuroprotection-and-repair
#4
REVIEW
Eric P Knott, Mazen Assi, Sudheendra N R Rao, Mousumi Ghosh, Damien D Pearse
A wide diversity of perturbations of the central nervous system (CNS) result in structural damage to the neuroarchitecture and cellular defects, which in turn are accompanied by neurological dysfunction and abortive endogenous neurorepair. Altering intracellular signaling pathways involved in inflammation and immune regulation, neural cell death, axon plasticity and remyelination has shown therapeutic benefit in experimental models of neurological disease and trauma. The second messengers, cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP), are two such intracellular signaling targets, the elevation of which has produced beneficial cellular effects within a range of CNS pathologies...
March 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28338398/dexamethasone-suppresses-jmjd3-gene-activation-via-a-putative-negative-glucocorticoid-response-element-and-maintains-integrity-of-tight-junctions-in-brain-microvascular-endothelial-cells
#5
Wonho Na, Jee Y Shin, Jee Y Lee, Sangyun Jeong, Won-Sun Kim, Tae Y Yune, Bong-Gun Ju
The blood-brain barrier (BBB) exhibits a highly selective permeability to support the homeostasis of the central nervous system (CNS). The tight junctions in the BBB microvascular endothelial cells seal the paracellular space to prevent diffusion. Thus, disruption of tight junctions results in harmful effects in CNS diseases and injuries. It has recently been demonstrated that glucocorticoids have beneficial effects on maintaining tight junctions in both in vitro cell and in vivo animal models. In the present study, we found that dexamethasone suppresses the expression of JMJD3, a histone H3K27 demethylase, via the recruitment of glucocorticoid receptor α (GRα) and nuclear receptor co-repressor (N-CoR) to the negative glucocorticoid response element (nGRE) in the upstream region of JMJD3 gene in brain microvascular endothelial cells subjected to TNFα treatment...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28338324/studies-to-examine-potential-tolerability-differences-between-the-5-ht2c-receptor-selective-agonists-lorcaserin-and-cp-809101
#6
Guy A Higgins, Leonardo B Silenieks, Amy Patrick, Ines A M De Lannoy, Paul J Fletcher, Linda A Parker, Neil J MacLusky, Laura C Sullivan, Teresa A Chavera, Kelly A Berg
Lorcaserin (LOR) is a selective 5-HT2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference...
March 24, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28337127/nlrp3-inflammasome-in-neurological-diseases-from-functions-to-therapies
#7
REVIEW
Limin Song, Lei Pei, Shanglong Yao, Yan Wu, You Shang
Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28337124/interleukin-4-protects-dopaminergic-neurons-in-vitro-but-is-dispensable-for-mptp-induced-neurodegeneration-in-vivo
#8
Laura Hühner, Jennifer Rilka, Ralf Gilsbach, Xiaolai Zhou, Venissa Machado, Björn Spittau
Microglia are involved in physiological as well as neuropathological processes in the central nervous system (CNS). Their functional states are often referred to as M1-like and M2-like activation, and are believed to contribute to neuroinflammation-mediated neurodegeneration or neuroprotection, respectively. Parkinson's disease (PD) is one the most common neurodegenerative disease and is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons in the substantia nigra resulting in bradykinesia, tremor, and rigidity...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28336953/palmitoylethanolamide-induces-microglia-changes-associated-with-increased-migration-and-phagocytic-activity-involvement-of-the-cb2-receptor
#9
F Guida, L Luongo, S Boccella, M E Giordano, R Romano, G Bellini, I Manzo, A Furiano, A Rizzo, R Imperatore, F A Iannotti, E D'Aniello, F Piscitelli, F Sca Rossi, L Cristino, V Di Marzo, V de Novellis, S Maione
The endogenous fatty acid amide palmitoylethanolamide (PEA) has been shown to exert anti-inflammatory actions mainly through inhibition of the release of pro-inflammatory molecules from mast cells, monocytes and macrophages. Indirect activation of the endocannabinoid (eCB) system is among the several mechanisms of action that have been proposed to underlie the different effects of PEA in vivo. In this study, we used cultured rat microglia and human macrophages to evaluate whether PEA affects eCB signaling. PEA was found to increase CB2 mRNA and protein expression through peroxisome proliferator-activated receptor-α (PPAR-α) activation...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28336575/pharmacologic-profile-of-naloxegol-a-peripherally-acting-%C3%A2%C2%B5-opioid-receptor-antagonist-for-the-treatment-of-opioid-induced-constipation
#10
Eike Floettmann, Khanh Bui, Mark Sostek, Kemal Payza, Michael Eldon
Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ-opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxone and a peripherally acting µ-opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol...
March 23, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28334745/disease-correction-by-aav-mediated-gene-therapy-in-a-new-mouse-model-of-mucopolysaccharidosis-type-iiid
#11
Carles Roca, Sandra Motas, Sara Marcó, Albert Ribera, Víctor Sánchez, Xavier Sánchez, Joan Bertolin, Xavier León, Jennifer Pérez, Miguel Garcia, Pilar Villacampa, Jesús Ruberte, Anna Pujol, Virginia Haurigot, Fatima Bosch
Gene therapy is a promising therapeutic alternative for Lysosomal Storage Disorders (LSD), as it is not necessary to correct the genetic defect in all cells of an organ to achieve therapeutically significant levels of enzyme in body fluids, from which non-transduced cells can uptake the protein correcting their enzymatic deficiency. Animal models are instrumental in the development of new treatments for LSD. Here we report the generation of the first mouse model of the LSD Muccopolysaccharidosis Type IIID (MPSIIID), also known as Sanfilippo syndrome type D...
February 17, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28330964/thermoregulatory-inversion-a-novel-thermoregulatory-paradigm
#12
Domenico Tupone, Georgina Cano, Shaun F Morrison
To maintain core body temperature in mammals, the normal CNS thermoregulatory reflex networks produce an increase in brown adipose tissue (BAT) thermogenesis in response to skin cooling, and an inhibition of the sympathetic outflow to BAT during skin rewarming. In contrast, these normal thermoregulatory reflexes appear to be inverted in hibernation/torpor: thermogenesis is inhibited during exposure to a cold environment, allowing dramatic reductions in core temperature and metabolism, and thermogenesis is activated during skin rewarming, contributing to a return of normal body temperature...
March 22, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28326567/both-standing-and-postural-threat-decrease-achilles-tendon-reflex-inhibition-from-tendon-electrical-stimulation
#13
Brian C Horslen, J Timothy Inglis, Jean-Sébastien Blouin, Mark G Carpenter
Golgi tendon organ Ib reflexes are thought to contribute to standing balance control, but it is unknown if they are modulated when people are exposed to a postural threat. We used a novel application of tendon electrical stimulation (TStim) to elicit Ib inhibitory reflexes in the medial gastrocnemius, while actively engaged in upright standing balance, to examine a) how Ib reflexes to TStim are influenced by upright stance, and b) the effects of height-induced postural threat on Ib reflexes during standing...
March 22, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28326017/adiponectin-regulates-the-polarization-and-function-of-microglia-via-ppar-%C3%AE-signaling-under-amyloid-%C3%AE-toxicity
#14
Juhyun Song, Seong-Min Choi, Byeong C Kim
Alzheimer's disease (AD), characterized by the abnormal accumulation of amyloid beta (Aβ), is gradually increasing globally. Given that AD is considered a neuroinflammatory disease, recent studies have focused on the cellular mechanisms in brain inflammatory conditions that underlie AD neuropathology. Microglia are macrophage cells in the central nervous system (CNS) that are activated in response to Aβ condition. The function of microglia contributes to the neuroinflammation in AD brain, suggesting that microglia regulate the production of inflammatory mediators and contribute to the regeneration of damaged tissues...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28325152/synthesis-computational-and-pharmacological-evaluation-of-n-2-benzoyl-4-chlorophenyl-2-4-substituted-phenyl-piperazin-1-yl-acetamides-as-cns-agents
#15
Shweta Verma, Surendra Kumar, Sushil Kumar
A series of new N-(2-benzoyl-4-chlorophenyl)-2-(4-(substituted phenyl) piperazin-1-yl) acetamides (3a-j) have been synthesized by the chloroacetylation of 2-amino-5-chlorbenzophenone which was further reacted with substituted phenylpiperazine. The chemical structures of the compounds were confirmed on the basis of their TLC, IR, 1HNMR, 13CNMR and by elemental analysis. The physicochemical similarity of the target compounds with respect to standard drug diazepam was assessed by calculating from a set of physicochemical properties using software programs...
March 21, 2017: Central Nervous System Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28324949/muscle-synergy-analysis-in-transtibial-amputee-during-ramp-ascending-activity
#16
P Mehryar, M S Shourijeh, H F Maqbool, M Torabi, A A Dehghani-Sanij
In developed countries, the highest number of amputees are elderly with transtibial amputation. Walking on inclined surfaces is difficult for amputees due to loss of muscle volume and strength thereby transtibial amputees (TA) rely on the intact limb to maintain stability. The aim of this study was to use the concatenated non-negative matrix factorization (CNMF) technique to calculate muscle synergy components and compare the difference in muscle synergies and their associated activation profiles in the healthy and amputee groups during ramp ascending (RA) activity...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28324647/metabolism-and-distribution-of-clozapine-n-oxide-implications-for-nonhuman-primate-chemogenetics
#17
Jessica Raper, J Scott Daniels, Ryan D Morrison, Leonard Howell, Jocelyne Bachevalier, Thomas Wichmann, Adriana Galvan
The use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in neuroscience has rapidly expanded in rodent studies, but has lagged behind in nonhuman primate (NHP) experiments, slowing the development of this method for therapeutic use in humans. One reason for the slow adoption of DREADD technology in primates is that the pharmacokinetic properties and bioavailability of clozapine-n-oxide (CNO), the most commonly used ligand for human muscarinic (hM) DREADDs, are not fully described in primates...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28323646/endothelial-cells-and-lymphatics-at-the-interface-between-the-immune-and-central-nervous-systems-implications-for-multiple-sclerosis
#18
Céline Meyer, Guillaume Martin-Blondel, Roland S Liblau
PURPOSE OF REVIEW: The central nervous system (CNS) has a unique relationship with the immune system. This review highlights the distinct roles of lymphatic vessels and endothelial cells in the interface between CNS and immune cells and invites to revisit the concept of CNS immune privilege. RECENT FINDINGS: T cells can follow several routes to penetrate the CNS parenchyma but may also benefit, together with antigen-loaded presenting cells, from the newly described lymphatic network to exit the CNS...
March 18, 2017: Current Opinion in Neurology
https://www.readbyqxmd.com/read/28323206/ligands-of-peroxisome-proliferator-activated-receptor-alpha-promote-glutamate-transporter-1-endocytosis-in-astrocytes
#19
Hui-Ting Huang, Chih-Kai Liao, Wen-Tai Chiu, Shun-Fen Tzeng
Astrocytes, a stellate-shape glial population in the central nervous system (CNS), maintain glutamate homeostasis in adult CNS by undergoing glutamate uptake at the synapse through their glutamate transporter-1 (GLT-1). Peroxisome proliferator-activated receptor-α (PPARα) can be activated by endogenous saturated fatty acids to regulate astrocytic lipid metabolism and functions. However, it is unclear if PPARα can exert the regulatory action on GLT-1 expression in astrocytes. This study showed that treatment with palmitic acid (PA) and the other two PPARα agonists (GW 7647 and WY 14,643) caused no change in the morphology of astrocytes, whereas membranous GLT-1 protein levels in astrocytes were significantly decreased by PA and PPARα agonists...
March 16, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28323108/chronic-methamphetamine-exposure-significantly-decreases-microglia-activation-in-the-arcuate-nucleus
#20
Steven A Lloyd, Beau Corkill, Matthew C Bruster, Rick L Roberts, Ryan A Shanks
Methamphetamine is a powerful psychostimulant drug and its use and abuse necessitates a better understanding of its neurobiobehavioral effects. The acute effects of binge dosing of methamphetamine on the neurons in the CNS are well studied. However, the long-term effects of chronic, low-dose methamphetamine are less well characterized, especially in other cell types and areas outside of the major dopamine pathways. Mice were administered 5mg/kg/day methamphetamine for ten days and brain tissue was analyzed using histochemistry and image analysis...
March 16, 2017: Journal of Chemical Neuroanatomy
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