Introduction to Central Nervous SystemCHEM E-120

2011

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Nervous System• Central Nervous System (CNS)

– Brain– Spinal cord– Processes and stores motor and sensory information• Important regions of the brain involved in psychiatric disorders– Cerebral Cortex - Frontal lobe, motor cortex– Limbic Lobe - drives, emotions, memory

• Hippocampus, Amygdala– Basal ganglia (movement control)

• Caudate nucleus• Lenticular nucleus

– putamen– globus pallidus

– Thalamus - functions as a relay to cortex– Hypothalamus- controls autonomic function

• Peripheral Nervous System (PNS)– Nerve network from (efferent) and to (afferent) the spinal cord, connects CNS

to muscles and organs

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Limbic System

• A group of interconnected structures (cells) that mediate emotions, learning and memory. Structures are interposed between the hypothalamus and neocortex.

• Amygdala and hippocampus– Primitive parts of the brain involved in behavioral control– Amygdala and its neural connections are centrally involved in emotional

experiences and responses. Receives specific sensory inputs of sight, sound, touch, smell, and taste, and more general sensory inputs of levels of physical and emotional comfort and discomfort.

– Hippocampus has a primary role in some forms of learning and memory.

• Hypothalamus– Connecting point in pathways concerned with autonomic, endocrine,

emotional, and somatic functions that are designed to maintain homeostasis. Function extends into drives and emotional behaviors.

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Figure 23-1 Three-dimensional reconstruction of the hypothalamus and surrounding cerebral structures. The hypothalamus has been rendered with a flat anterior surface because the preoptic area (see Fig. 23-4), which envelops the anterior end of the third ventricle but is in front of the plane sometimes used to separate the diencephalon and telencephalon, was not included. *, claustrum; Am, amygdala; Ca, caudate nucleus; CC, corpus callosum; GP, globus pallidus; Hy, hypothalamus; IC, internal capsule; In, insula; LVa, anterior horn of the lateral ventricle; P, putamen; Th, thalamus.

Limbic System

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Figure 23-15 Three-dimensional re-construction of the hippocampus, fornix, and amygdala inside a translucent CNS, seen from the left (A), above (B), in front (C), and behind (D).

Limbic System

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Figure 23-18 Major inputs to the basolateral (blue), central (red), and medial (green) nuclei of the amygdala (Am). Only inputs from visual association cortex to the basolateral nuclei are shown, although there are similar projections from most or all unimodal sensory areas. The inputs from limbic cortex to the basolateral nuclei also include a major projection from the

insula, which is not present in this view. B, brainstem (periaqueductal gray, parabrachial nuclei, other nuclei); Hy, hypothalamus; S, septal nuclei; T, thalamus (multiple nuclei). (Modified from Warwick R, Williams PL: Gray's anatomy, Br ed 35, Philadelphia, 1973, WB Saunders.)

Neuronal Inputs to the Amygdala

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Figure 23-21 Major outputs from the basolateral (blue), central (red), and medial (green) nuclei of the amygdala (Am). These take three routes: (1) the stria terminalis, which reaches the septal nuclei (S) and hypothalamus (Hy); (2) the ventral amygdalofugal pathway (see Fig. 23-20B and C) to the hypothalamus (Hy), thalamus (T; mainly the dorsomedial nucleus),

widespread areas of ventromedial prefrontal and insular cortex, ventral striatum (VS), olfactory structures, and various brainstem sites (B); and (3) direct projections to the hippocampus (HC) and temporal and other neocortical areas. Only visual cortical areas are shown, although there are similar projections to most or all primary and unimodal sensory areas. (Modified

from Warwick R, Williams PL: Gray's anatomy, Br ed 35, Philadelphia, 1973, WB Saunders.)

Neuronal Outputs from the Amygadala

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Cells in the CNSDiverse cell types organized into assemblies and patterns such that specialized components are integrated into the physiology of the whole organ.

Neurons - most polymorphic cell in the human body (relay information)• 6 - 80 µm in diameter• Axons - emerge from one pole of the cell body (white matter, lipid myelin sheath)

• send information

• Dendrites - emerge from the opposite pole of the cell• receive information

• neurons interact via a synapse

Neuroglia (metabolic and structural support)• 3 main types• Contain no synaptic junction• Main cells of blood-brain-barrier• 10 - 50 times more glia the neuron cells

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Figure 1-4 Examples of multipolar (A to E), bipolar (F), and unipolar (G) neurons, all drawn to about the same scale to demonstrate the range of neuronal sizes and shapes. All were stained by the Golgi method;

dendrites are indicated by green arrows, axons by blue arrows.

A, Purkinje cell from the cerebellar cortex. B, Granule cell from the cerebellar cortex. C, Projection neuron from the inferior olivary nucleus. D, Spinal cord motor neuron. E, Large pyramidal neuron from the cerebral cortex. F, Olfactory receptor neurons. G, Dorsal root ganglion cells (whose processes have axonal properties along almost their entire course). The tiny inset at the upper right shows the actual size of the pyramidal neuron.

(Modified from Ramón y Cajal S: Histologie du système nerveux de l'homme et des vertébrés, Paris, 1909, 1911, Maloine.)

Neuron Size and Shape

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Synapse

Gap between two neurons (axon-dendrite) across which neurotransmitters diffuse.

Excitory synapseInhibitory synapseModulatory synapse

20 - 40 nm gap - (electrical synapse 3.5 nm)

Presynaptic nerve terminal postsynaptic nerve terminal

Presynaptic and Postsynaptic nerve terminals contain cell surface proteins which interact with neurotransmitters and ions.

Presynaptic neuron transmitts the signalPostsynaptic neuron receives a signal

Most drugs elicit a response via interactions at the synapse

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Figure 1-3 Schematic view of a typical neuron, indicating synaptic inputs to its dendrites (although other sites are possible) and information flow down its axon, reaching synaptic endings on other neurons. Information flow is unidirectional due to molecular specializations of various parts of neurons. The pink segments covering the axon represent the myelin sheath that coats many axons, and the gap in the axon represents a missing extent that might be as long as a meter in the longest axons.

Neuron

Cell Body

Axon contains proteins called kinesin anddynenin (molecular motors) that transportorganelles, mRNA and signaling moleculesfrom the cell body to axonal terminus

Node of Ranvier

Presynapticterminal

Postsynaptic dendrite

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FIGURE 1-9 A dendrite (D) is flanked by two axon terminals packed with clear, spherical synaptic vesicles. Details of the synaptic region are clearly shown. ×75,000. (Basic Neurochemistry)

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Action Potential

An electrical signal (velocity of 1-100 m/sec) produced in a neuron by a change in ion concentrations. Action potentials are the signals by which the brain receives , analyzes, and conveys information.

Though the action potential is electrical in nature, the signal is relayed via neurotransmitters across the synapse.

At equilibrium, the cell membrane of the neuron has an overall negative charge relative to the exterior of the cell due to K+ ions leaking out of the cell.

resting membrane potential - -40 to -90 mV (~ -65 mV)

Ion Extracelluar concentration (mM) Intracellular concentration (mM)

Na+ 140 15K+ 4 130Ca2+ 2.5 1-2 (sequestered)Cl- 120 5

See Kandel Chapter 2

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Action Potential

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A stimulatory signal (e.g. neurotransmitter (1), voltage change) results in opening of Na+ channels. Neuron becomes more (+) - depolarization, at a certain potential (threshold) the cell will “fire an action potential” down the axon.When the potential reaches the axon terminus - neurotramsmitter release.Increase in membrane potential (hyperpolarization) - inhibitory response

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Blood-Brain Barrier (BBB)

A physical barrier that controls the movement of chemicals from extracellular fluid in the body (blood) into the extracellular fluid of the brain.

In the brain the endothelial cells in blood capillaries form a very tight junction that prevents many chemicals from passive diffusion across the capillary cell membrane into the brain.

Lipid-soluble substances can often diffuse across BBB

Active transporters exist in the capillary cell membraneglucoseamino acidshormones

Efflux transporters P-glycoprotein (P-gp)

MRPOrganic anion transporters (OAT3)

Transporters can be on blood side or CNS side of membranes.

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Figure 6-27 Barrier systems in and around the brain. Substances can leave extracerebral capillaries but are then blocked by the arachnoid barrier. They can also leave choroidal capillaries but are then blocked by the choroid epithelium. They cannot leave any other capillaries that are inside the arachnoid barrier (except for those in the circumventricular organs). The ventricular and subarachnoid spaces are in free communication with each other, and both communicate with the extracellular spaces of the brain.

Brain Barrier Systems

3 distinct membrane (meninges) layers surround the brain. The meninges are connected to the skull. The brain is mechanically suspended withinthe meninges.

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Figure 6-28 CNS capillaries with and without barrier properties. A, Capillary in a hypothalamic nucleus (supraoptic nucleus) of a rat. The continuous endothelial wall and the lack of pinocytotic vesicles are apparent; tight junctions are also present between endothelial cells but cannot be seen at this magnification. B, Capillary in the subfornical organ, which is a circumventricular organ near the roof of the third ventricle adjacent to the interventricular foramen. The walls of this capillary are quite permeable and are characterized by fenestrations (f), pinocytotic vesicles (v), and substantial spaces (s) around the capillary. (From Gross PM: Brain Res Bull 15:65, 1985.)

BBB in Capillary Cell

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BBB in Capillary Cell

Cerebral endothelial cells are unique in that they form complex tight junctions (TJ) produced by the interaction ofseveral transmembrane proteins that effectively seal the paracellular pathway. These complex molecular junctions make the brain practically inaccessible for polar molecules, unless they are transferred by transport pathways of the BBB that regulate the microenvironment of the brain. There are also adherens junctions (AJ), which stabilize cell–cell interactions in the junctional zone. In addition, the presence of intracellular and extracellular enzymes such as monoamine oxidase (MAO), γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase, peptidases, nucleotidasesand several cytochrome P450 enzymes endow this dynamic interface with metabolic activity. Large molecules such as antibodies, lipoproteins, proteins and peptides can also be transferred to the central compartment by receptor-mediated transcytosis or non-specific adsorptive-mediated transcytosis. The receptors for insulin, low-density lipoprotein (LDL), iron transferrin (Tf) and leptin are all involved in transcytosis. P-gp, P-glycoprotein; MRP, multidrug resistance associated protein family.

Nature Reviews Drug Discovery 2007, 6, 650

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Neurotransmitters

• Chemicals that are synthesized in a neuron and stored in synaptic vesicles. Released upon stimulation of the neuron and interact with another neuron through the synapse

• Function is to transmit and regulate information• Act upon receptors

– Dopamine binds to a dopamine receptor

• Not uniformly distributed throughout CNS• A neuron can contain several neurotransmitters and receptors• Regulated by feedback mechanisms• Release from synaptic vesicles is activated by Ca2+

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Neurotransmitters - Criteria

1. The chemical must be found in the presynaptic neuron and must be released when the neuron is stimulated.

2. The chemical must be inactivated after it is released.reuptakedegradation

3. If the chemical is applied exogenously at the postsynapticmembrane, the effect will be the same as when the presynapticneuron is stimulated.

4. The chemical applied to the synapse must be affected in a manner similar to that of the naturally occurring chemical

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Neurotransmitters - Classification

Cholinegeric System Acetylcholine (Ach)

Monoamine System Dopamine (D)Norepinephrine (NE)Epinephrine (E)Serotonin (HT)

Amino Acids - aminobutyric acid (GABA) inhibitoryGlutamate (Glu) excitoryGylcine (Gly)Aspartate (Asp)

Neuropeptides EnkephalinsEndophinsSubstance P

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Neurotransmitters - Acetylcholine

The neurotransmitter in the cholinergic system

Binds to two receptors:

Muscarinic acetylcholine receptor (M)G-protein coupled receptor

Nicotinic acetylcholine receptor (nAChR) ligand-gated Na+ ion channel

Foye: Chapter 12

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Neurotransmitters – Cholinergic System

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Neurotransmitters - Muscarinic Ach receptors

M1 Gq/11, increases phospholipase C activity↑ Cognitive function

↑Seizure activity

↑Secretions

↑ Autonomic ganglia depolarization

↓ DA release and locomotion

M3 Gq/11↑ Food intake, body fat deposits

Inhibits dopamine release

Synthesis of nitric oxide

M5 Gq/11Facilitates dopamine release

Augments drug seeking behavior and reward

M2 Gi/Go decreases adenylyl cyclase activity and

increases K+ currents, decreases Ca2+ currents

Neural inhibition in CNS

↑ Tremors

hypothermia & analgesia

M4 Gi/Gonhibition of autoreceptor- and heteroreceptor-mediated transmitter release in CNS

Analgesia

Cataleptic activity;

Facilitates dopamine release

Foye p 365

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Neurotransmitters - Nicotinic ACh receptors

CNS - 5 transmembrane proteins that are composed of and/or subunits. Each subunit contains 4 segments.

Related in structure and sequence to GABA, glycine, 5HT3 receptors

2-10 subunit that binds acetylcholine2-4

42 subunit predominates in the CNS

(4)2 (4)3 agonist inc Na+ and K+ permeability(7)5 agonist inc Ca2+ permeability

Function at presynaptic locations to regulate release of Glu, D, HT, Ach, and neuropeptides

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Monoamine System

Monoamine unbalance often plays a major role in the etiology of psychiatric disorders.

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Neurotransmitters - Dopamine

Phenotype effects in knockout mice

D1 reduced agonist response, hyperlocomotionD2 Parkinsonian-like motor impairmentD3 HyperactivityD4 reduced locomotion, hypersensitivity to ethanol and stimulantsD5 reduced agonist induced locomotion, startle, and prepulse inhibition

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2 families of dopamine binding receptors

D1-like (increase cAMP) D2-like decrease cAMP, open K+ channels, close Ca2+ channels

D1, D5 D2, D3, D4

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Neurotransmitters - Dopamine

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Neurotransmitters - Norepinephrine/ Epinephrine

Bind to GPCR adrenergic receptors. Role in CNS not clearly understood.

1A 1B 1D 2A 2B 2C 1 2 3

Amino acids

430-476 515 560 450 450 461 477 413 402/408

Effector pathways

↑Ca2+ PKC ↑Ca2+ PKC

↑Ca2+ PKC

↓cAMP ↓cAMP ↓cAMP ↑cAMP ↑cAMP ↑cAMP

Distribution Heart, ,liver

cereb , ellumcerebr al

,cortex blood

vessels

Spleen, k ,idney fetal

,brain blood

vessels

Arota, cerebr alcortex

Pancreas, small

, intestine locus

cerules, hippocampus

Liver, thalamus

Heart, , lung,aorta

,hippocampus olfactory bulb

Heart, ,kidney

cerebr al,cortex

hypothalamus

Lung, liver, cereb , ellumhippocampus, cerebr al

,cortex smooth

muscle, olfactory bulb

F ,at brain (?)

Knockout phenotypes (mouse)

↓ blood pressure

↓ blood pressure, response toCN S

stimulants

↓ blood pressure

Increas esympathetic

&activity tachycardia,

Decre ased vasoconstrictor

response to 2 agonists

No ov ertphenotype

M ostdie prenatally

C hangesin vascular tone

and energ ymetabolism

during stress

Altered leptin and insulin

concentrations after agonist treatment

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beta-blockers for treatmenthypertension

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Neurotransmitters - Norepinephrine

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Neurotransmitters - Serotonin

Binds to the serotonin receptor and transporterImportant in depression, anxiety, and schizophrenia

3 main families

5-HT1 - GPCR, 5 subtypes have 40-60% sequence homology, inhibit adenylyl cyclase5-HT2 - GPCR, 3 subtypes have 45-50% sequence homology, stimulate phospholipase C5-HT3 - ligand-gated ion channel, 6 subtypes, stimulate adenylyl cyclase

Indole ethylamine

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Neurotransmitters - Serotonin

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Monoamine Transporters

Very important mechanism to reduce the concentration of theneurotransmitter in the synapse by reuptake into the presynaptic terminus.

DAT - dopamine transporter localized on dopamine neuronNET - norepinephrine transporter localized on adrenergic neuronsVMAT-2 - vesicular membrane transporter - concentrates catecholamines in vesicules in the presynaptic neuron

NET DAT VMAT-2

Mechanism NaCl-dependent NaCl-dependent H+-dependent

Amino acids 617 620 742

Chromosome 16 5 10

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Neurotransmitters - GABA

Major inhibitory neurotransmitter - mM concentrations

GABAA - ligand-gated Cl- ion channel

GABAB - GPCR with structural similarity to glutamate receptorsfound on terminals of neurons that use other transmitters (norepinephrine, dopamine, serotonin)

Presynaptic activation of GABAB decreases release of other transmittersGABAB receptors exist as heterodimers

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GABAA Receptor

and subunits determine pharmacological specificity at theGABA and BZ sites while the subunits are necessary for BZ binding

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Neurotransmitters - GABA

High_Yield NeuroAnatomy p155

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Neurotransmitters - Glutamate

Major excitory neurotransmitter in the brain.Excites ~ 90% of all neuron ~ 80-90% of allsynapses are glutamatergic.Concentrations range from 4-15 mol/g tissue

Glutamate receptors:

1. Ionotropic - ligand-gated ion channels that areopened upon binding of glutamate

3 classes: NMDA (EC50 = 1 mol/l), AMPA (EC50 = 400 mol/l), KA

2. Metabotropic GPCR8 classes: mGluR1 - mGluR8

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Neurotransmitters - Glutamate

High_Yield NeuroAnatomy p156

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G-protein Coupled Receptor – GPCRMembrane bound receptor bound to a G-protein that is in the cytoplasm

7 transmembrane domainsReceptor 3 extracellular domains

3 intracellular domains

three distinct subunits , , G-protein bind to GTP and GDP

Gs - stimulation of adenyl cyclaseGi - inhibition of adenyl cyclase

~ 60% of drugs act on GPCR’s

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Cell Surface Proteins

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G-protein Coupled Receptor - GPCR

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Neurotransmitters - Muscarinic Ach receptors

Siegal Basic Neurochemistry

FIGURE 11-11 Predicted amino acid sequence and transmembrane domain structure of the human M1 muscarinic receptor. Amino acids that are identical among the m1, m2, m3 and m4 receptors are dark orange. The shaded cloud represents the approximate region that determines receptor G-protein coupling. Arrows denote amino acids important for specifying G protein coupling. Amino acids predicted to be involved in agonist or antagonist binding are denoted by white letters [50].

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Cell Surface Proteins - Transporter

SERT has ~ 50%homology with DAT/NET

SERT located on serotonergic neurons

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Receptors vs transporters

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Cell Surface Proteins – Ion channels

When ACh or agonists bind to nicotinic ACh receptors the channel open to a diameter of 6.5Å. Selective for Na+ and K+

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ligand-gated ion channelsvoltage-gated ion channels

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GABAA Receptor – Ligand Gated Ion Channel

Possible sites of binding of alcoholα1β2γ2α4β1δα4β3δα6β3δactivity β3 > β2δ KO mice drink less alcohol

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FIGURE 10-1 Depolarization opens voltage-sensitive Ca2+ channels in the presynaptic nerve terminal (1). The influx of Ca2+ and the resulting high Ca2+ concentrations at active zones on the plasmalemma trigger (2) the exocytosis of small synaptic vesicles that store neurotransmitter (NT) involved in fast neurotransmission. Released neurotransmitter interacts with receptors in the postsynaptic membrane that either couple directly with ion channels (3) or act through second messengers, such as (4) G-protein-coupled receptors. Neurotransmitter receptors, also in the presynaptic nerve terminal membrane (5), either inhibit or enhance exocytosis upon subsequent depolarization. Released neurotransmitter is inactivated by reuptake into the nerve terminal by (6) a transport protein coupled to the Na+ gradient, for example, dopamine, norepinephrine, glutamate and GABA; by (7) degradation (acetylcholine, peptides); or by (8) uptake and metabolism by glial cells (glutamate). The synaptic vesicle membrane is recycled by (9) clathrin-mediated endocytosis. Neuropeptides and proteins are stored in (10) larger, dense core granules within the nerve terminal These dense core granules are released from (11) sites distinct from active zones after repetitive stimulation.

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