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* Cholinergic neurons<ref> Imeri L, Opp MR. How (and why) the immune system makes us sleep. Nat Rev
* Cholinergic neurons<ref> Imeri L, Opp MR. How (and why) the immune system makes us sleep. Nat Rev
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* This inhibitors are used to reverse muscle relaxants and sometimes to treat Alzheimer's disease<ref>Lindstrom J. Nicotinic acetylcholine receptors in health and disease. Mol
* This inhibitors are used to reverse muscle relaxants and sometimes to treat Alzheimer's disease<ref>Lindstrom J. Nicotinic acetylcholine receptors in health and disease. Mol
Neurobiol. 1997 Oct;15(2):193-222. Review. PubMed PMID: 9396010.</ref>
Neurobiol. 1997 Oct;15(2):193-222. Review. PubMed PMID: 9396010.</ref>
===='''Acetylcholine Receptors (AChR's)'''====
===='''Acetylcholine Receptors (AChR's)'''====
Revision as of 22:29, 10 May 2011
- 1 The Neuromuscular Junction
- 2 Introduction
- 3 History
- 4 Mechanism of action
- 5 Important Structural Components
- 6 Development of the neuromuscular junction
- 7 Common neuromuscular junction disorders
- 8 Current associated research
- 9 Future research
- 10 External links
- 11 Glossary
- 12 References
The Neuromuscular Junction
A Neuromuscular junction (NMJ) is a connection between an axon of a motor neuron and the motor end plates on a muscle fibre. The NMJ can be found in both smooth and skeletal muscle fibres, with different purpose and mechanisms which may involve different receptors. Starting with historic researches, this group project establishes detailed information on how this junction works, which may lead to a skeletal muscle contraction, followed by a description for each of its engines involved during this process. Additionally, the NMJ is the site of some well-known diseases which will be briefly described in a table of NMJ's disorders. Currently, the NMJ is a research topic in many areas such as pharmacology, pathology, physiology and medicine.
Historic researchers in NMJ:
In 1672, Myasthenia gravis (MG) was first described by Thomas Willis. It is an acquired autoimmune disease with antibodies against the nicotinic acetylcholine receptor (AChR) at the NMJ. [1]
In 1842, Claude Bernard concluded that the arrow poison 'curare' acts at the NMJ to interrupt the stimulation of muscle by nerve impulses. [2]
In 1850, Claude Bernard demonstrated that paralysis was mediated via the NMJ, although the precise mechanism remained unknown. [3]
In 1914, Sir Henry Dale, (in 1936, he was warded the Nobel Prize for Medicine and Physiology), investigating the pharmacological properties of acetylcholine (ACh), distinguished two actions that were reproduced by the alkaloids, muscarine and nicotine. As the effects of muscarine mimicked the parasympathetic nervous system, he termed the receptors muscarinic, whereas those in autonomic ganglia and at the skeletal NMJ were termed nicotinic. [4]
In 1936, The release of ACh into the NMJ has been demonstrated at vertebrate motor nerve endings when stimulated. [5]
In 1949, At the Paris conference Jack C. Eccles was convinced of the part played by acetylcholine at the neuromuscular junction but still thought of electric currents as being responsible for excitation and inhibition in the central nervous system. [6]
In 1952 - 1954, the name end-plate potential is used since Fatt&Katz (1952) and Del Castillo & Katz (1954) studied the endplate potential (epp) at NMJ. They concluded that the ACh molecules were released in packets containing several thousand ACh molecules revealing the quantal nature of synaptic transmission.[7] [8]
In 1966, Bernard Katz and colleagues showed that the neurotransmitter ACh is releaased in quantal vesicles. [9]
In 1978, it has been demonstrated in frog muscles that nerve terminals persist at synaptic sites on basal lamina sheaths in frogs following degeneration of muscle fibers. The conclusion was that factors that guide axon's growth are present at synaptic sites outside of myofiber. Axons can differentiate into nerve terminals even when the postsynaptic myofibers are absent.[10]
In 1981, it was first recognized that the formation of NMJ involve complex signalling between nerve and muscle cells. [11]
In 1986, M. John Anderson experiments with Xenopus laevis embryos and observes that proteolytic enzyme systems used in tissue remodeling may also contribute to nerve and muscle cell interaction during synaptogenesis. [12]
In 1990, Agrin has been first identified to cause AChR cluster in cultured myotubes. [13] It has since been described to play a crucial role in the development of neuromuscular junction.
In 2000, Discovery of the Rabies virus entry at the neuromuscular junction in nerve-muscle cocultures. [14]
Mechanism of action
The mechanism of action of NMJ involves many steps and engines which harmonically follow each other in which the ability of a muscle to contract or relax depend on. this process starts with a nerve impulse that reaches the motor nerve terminal and triggers the opening of specialized ion protein channels. Then, the Calcium ions rush through the opening into the axon terminal, prompting the formation and release of acetylcholine synaptic vessicles. Followed by the fusion of the vessicle membranes with the nerve terminal membrane and release acetylcholine (ACh) into the neuromuscular junction gap. ACh then binds with receptors. This chemical binding induces the release of sodium ions which enter the muscle and depolarize across the membrane. End-plate potential then opens voltage-sensitive sodium channels at the synaptic fold, initiating an action potential that propagates along the muscle fibre in each direction and causes the muscle to contract. Acetylcholine receptor pores then close. Acetylcholine is broken down and recycled.
- Nerve impulse reaches the motor nerve terminal[15]
- Specialized proteins forming ion channels in its cell membrane open quickly[16]
- Calcium enters into the axon terminal[17]
- Synaptic vesicles are filled with ACh[18]
- Ca causes some of the vesicle membranes to fuse with the nerve terminal membrane[19]
- ACh content is released into synaptic cleft[20]
- ACh diffuses rapidly across the gap and binds to the ACh receptors (AChRs)[21]
- When this binding occur, small positively charged sodium (Na) ions enter the muscle[22]
- This lead to the depolarization across membrane[23]
- End-plate potential in turn opens the voltage-sensitive Na channels at the synaptic fold[24]
- An "all or nothing" action potential starts which propagates along the muscle fibre in each direction[25]
- Initiation of a muscle contraction occur[26]
- Then, the AChR pore closes[27]
- ACh unbinds and broken down [28]
Motor neuron
Motor neurons are efferent neurons that carry impulses away from the Central Nervous System which innervate skeletal muscle to cause movement. They originate in the ventral horn of the spinal cord [29] and synapse with muscle fibres and carry information from the central nervous system to muscles, facilitating muscle contraction.
- Synapse with muscle fibres[30]
- Carry information from the central nervous system to muscles[31]
- Facilitate muscle contraction
- Somatic once are directly involved in the contraction of skeletal muscles[32]
- Excitatory
- Influenced by input descending from the brain[33]
- Affected by a class of diseases[34]. Motor neurone disease is a chronic degenerative disorder that affects both lower motor neurones and the descending tracts to the spinal cord. Degeneration of ventral horn cells causes weakness, wasting, hypotonia and fasciculation of the limb muscles known as progressive muscular atrophy.
- Amyotrophic lateral sclerosis is characterized by loss of lower neurons in spinal cord and brain stem and upper motor neurons that project in corticospinal tracts. Skeletal muscles innervated by the degenerated lower motor neurons show neurogenic atrophy.[35]
Acetylcholine (ACh)
- Cholinergic neurons[36]
- Skeletal muscle movement
- Regulation of smooth muscle
- One of the principle neurotransmitters of the peripheral nervous system
- Released by a motor neuron at the NMJ[37]
- Bind and activate a receptor protein[38]
- A very effective deliverer of sodium ions, which stimulate muscle contractions and excites nerves[39]
- The enzyme acetycholinesterase (AChE) hydrolyzes acetylcholine into acetic acid and choline[40]
- Choline travels back to be recycled into acetylcholine and start the process over again[41]
- Concentration of ACh remains higher if the AChE is inhibited[42]
- AChE inhibitors delay the degradation of acetylcholine[43]
- This inhibitors are used to reverse muscle relaxants and sometimes to treat Alzheimer's disease[44]
Acetylcholine Receptors (AChR's)
There are two main types of AChRs. Nicotinic AChRs, or nAChRs, are ionotropic receptors located between neurons and also in the neuromuscule synapse. Thay control skeletal muscle contraction. Muscarinic AChRs, or mAChRs, are metabotropic receptors located at the synapses of nerves with smooth or cardiac muscle. They control smooth muscle contraction by triggering signal transduction.
Nicotinic and Muscarinic receptors are receptors for acetylcholine. The important difference between the two is their mode of action
- Nicotinic receptors (nAChRs)
-Controls skeletal muscle contraction [45]
-located at synapses between two neurons and at synapses between neurons and skeletal muscle cells
- Muscarinic receptors (mAChRs)
-Controls smooth muscle contraction[46]
-Metabotropic receptors (G-protein coupled receptors)
-located at the synapses of nerves with smooth or cardiac muscle
-Trigger a chain of chemical events referred to as signal transduction
-Excitation and inhibition response
-Response of mAChRs is slower
For more information on nAChRs and mAChRs see: Nicotinic and Muscarinic Acetylcholine Receptors
Motor End Plate
The motor endplate (also known as the myoneural junction) is a specialized region of the sarcolemma. It is highly folded for increased surface area and contains a high concentration of AChRs. It receives neurotransmiters in order to propagate action potentials. It is responsible for the terminal tree like branching muscle fibre motor axons, and maintains muscle tone through the stretch reflex.
- Specialised region of the sarcolemma
- Highly folded
- Holds a high concentration of AChRs [47]
- Also called Myoneural Junction [48]
- Receive neurotransmitters in order to propagate an Action Potential [49]
- Responsible for the terminal tree like branching of a motor axon on a muscle fibre [50]
- Maintains muscle tone through stretch reflex [51]
Important Structural Components
Table of components
|Presynaptic membrane
|The presynaptic membrane is the membrane of the neuron that faces the membrane of the muscle. In between these two membranes is the synaptic cleft
|In a NMJ, the presynaptic membrane is the axon terminal. This is where the nerve axon terminates. The axon terminal contains many ion channels for the intake of Ca+ and also is responsible for exocytosis of acetylcholine vesicles into the synaptic cleft
|Synaptic cleft
|The space between the presynaptic membrane (axon terminal) and the postsynaptic membrane (motor end plate)
|Separates the presynaptic from the post synaptic cells, the electrical signal cannot cross this space from the neuron, but activates a chain of reactions that causes the muscle to contract. [52]
|Synaptic vesicles
|Found within the axon terminals of the neuron
|The synaptic vesicles are membranous organelles that contain the neurotransmitter Acetylcholine (Ach). They are released from the presynaptic membrane through exocytosis. Ach is released when it fuses with the postsynaptic membrane.[53]
|Ion gated channels and receptors
|Ion gated channels and receptors are located on the presynaptic membrane (axon terminal) and on the postsynaptic membrane (motor end plate)
|The depolarisation/repolarisation of the NMJ membrane is controlled by sodium, potassium, calcium, and chlorine ion channels. These channels are either opened or closed in response to certain chemical or voltage changes. The release of ions into the presynaptic membrane, synaptic cleft and postsynaptic membrane controls the depolarisation of the membrane and thus an action potential occurring.
|Postsynaptic membrane
|Separated from presynaptic membrane by synaptic cleft
|In the NMJ, the postsynaptic membrane is the motor end plate. Myonuclei are located underneath this membrane where they locally synthesise AChRs and other postsynaptic proteins. MuSK provides a structural scaffold necessary to initiate aggregates of postsynaptic molecules. Characterised by the accumulation of nAChRs and voltage-gated sodium channels. [54]
|Schwann Cell
|Schwann cells wrap around axons of neurons to form the myelin sheath and help in nerve impulse conduction.
|A single segment of an axon's myelin sheath is made up by a single Schwann cell which arranges themselves in a series of cylinders that serves as a guide for sprouts of regenerating axons.
|Mitochondria are concentrated within the presynaptic nerve terminal at both peripheral and central synapses. They are presumably related to the transmitter release machinery.[55]
|The key role of presynaptic mitochondria is to provide ATP for the assembly of actin cytoskeleton involved in the assembly of the presynaptic specialization including the clustering of SVs and mitochondria themselves.[56]
|Basal lamina (BL)
|Surrounds the Schwann cells of the axon and muscle fibre, Projects into folds that enclose the postsynaptic membrane
|Layer of extracellular matrix, Synaptic cleft is filled with dense BL, Contain ACh-esterase, Lamina densa comprising the intermediate part of BL, procollagen type 4 is the most important component [57]
Light microscopy and electron microscopy pictures of the Neuromuscular Junction
This is a light microscopy image of a neuromuscular junction. You can see the striated muscle fiber on the left hand side with the neuron that innervates this muscle fiber on the right. Light microscopy was invented around the 1600's and was the first type of microscope used by scientists. [58] The image from an optical microscope can be captured by a normal camera to generate a micrograph. Digital microscopes are available which just use a CCD camera to examine a sample, and the image is shown directly on a computer screen without the need for eyepieces. The main limitations with light microscopy is that the maximum normal magnification only reach around 1000x normal. [59]
Benefits of light microscopy:
- Cheap
- Simple to use
- Gives good detail to very small objects
- Can view living specimens (as opposed to the electron microscope where specimens need to be fixed)
- Can view specimens in colour (as opposed to the electron microscope where specimens are in black and white)
This is a scanning electron micrograph of a neuromuscular junction. This type of microscope was invented in the 1930's. The scanning electron microscope uses electrons to scan a sample which can be magnified from about 10 times to more than 500,000 times, which is about 250 times the highest magnification of light microscopes. [60] In the following two pictures you can see the highly folded region of the post synaptic membrane (motor end plate) where the neuron synapses with the muscle fiber. These folds increase the surface area of the junction and thus the number of available acetylcholine receptors. The increased number of AchR's allows the membrane to depolarise more quickly so the muscle fiber is activated to contract in a smaller period of time. More AChR's are also needed for the membrane potential to reach threshold so an action potential can propagate. [61]
Advantages of Electron microscopy:
- Higher resolution and magnification
- Capability to observe inside of samples
- Greater depth of field, creating more of a 3D image
- Finer magnification control, to be able to view a wider range of magnifications instead of a set 100x to 400x
Differences between scanning EM and transmission EM:
-Scans a beam of electrons across the object (does not penetrate the object)
-Measures energy from the electrons to create a three-dimensional picture of the surface of an object
-Able to produce images of larger objects (eg an ant)
-The SEM can magnify up to 200,000x
-Passes a beam of electrons THROUGH a specimen
-Can view inside objects
-The TEM can magnify up to 1,000,000x
Cellular organization of skeletal muscle:
The NMJ innervates muscle to contract, the following points outline the components of skeletal muscle:
- Epimysium, an external sheath of dense connective tissue surrounds the entire skeletal muscle
- Muscle fibers are arranged in regular bundles
- The connective tissue, perimysium surrounds each bundle
- Each fiber is surround by a delicate connective tissue called endomysium which is mainly composed of basal lamina and reticular fibers
The sliding filament theory of muscle contraction video. Click here
Muscle fibers:
- Muscle fibers are characterized by the presence of multiple nuclei located below the sarcolemma. The fibers contain sarcoplasm, a semifluid cytoplasm filled with mitochondria and myofibrils. Filaments lie parallel to the long axis of the myofibrils. Each myofibril is surrounded by the sarcoplasmic reticulum. The sarcoplasmic reticulum is a saclike membranous network associated with transverse tubules which are connected with the sarcolemma. Transverse tubules, or T-tubules, help to transmit signals from the sarcolemma to the myofibrils.
- Skeletal muscle must continuously make ATP to provide the energy for muscle contraction. There are three principal ways where a muscle fibre forms ATP:
1. ATP produced by phosphorylation of ADP by creatine phosphate which its phosphate in can be transferred to ADP to form ATP in a process called substrate phosphorylation. The result is 1 ATP per creatine phosphate molecule.
2. ATP produced by glycolytic processes which results in 2 Pyruvic acids and 2ATP per glucose.
3. ATP produced through Krebs cycle and oxidative processes in the mitochondria. There 36 ATP produced per glucose.
Proteins of muscle filaments:
- Actin
The function of the actin depends on a dynamic equilibrium between the actin filaments and the pool of actin monomers. Many actin filaments are unstable, but by associating with other proteins they can form stable structures in cells such as the contractile apparatus of muscles. They can form permanent structures such as microvilli and also form temporary structures such as contractile rings that pinch the cytoplasm in two when the cell divides. Additionally many protein bind to actin and modify its properties, regulate actin polymerization and create different structures.
The structure of actin is as follows:
- long filamentous polymers
- consists of two strands of globular monumers
- diameter 5.6nm
- twisted around each other
- double helical formation
- each monomer contain a binding site for myosin
- Myosin
There are two types of the myosin: myosin I and myosin II. Myosin I is found in all cells and it is one headed domain while myosin II is found in muscle cells and it is a dimer (two heads) that bind to each other to form myosin filaments. Aditionally, myosin bind to and hydrolise ATP which provides energy for their movement along actin filaments. The dissociation of the myosin results into two idental heavy chains and two pairs of light chains. The ATP-binding sites are located in the heads of heavy chains, enabling ATPase activity and actin binding. Myosin plays a vital role in muscle contraction and cell motility.
The structure of the myosin is as follows:
- large complex
- heavy chains are thin, rod-like molecules which are twisted together
- the heads of heavy chains have ATP-binding sites, ATPase activity and the ability to bind to actin
- the light chains are associated with the head
- Troponin (Tn)
Tn binds to the surface of tropomyosin (Tm). The Tn complex consists of three subunits:
1. TnT: attaches to tropomyosin
2. TnC: binds Ca ions
3. TnI: inhibits the actin-myosin interaction
- Tropomyosin (Tm)
Tm's principal function is to deliberate the cooperativity upon the Tn, so that Calcium switching of one Tn can control the activity of many actins. The Tm's structure is characterised by a long thin molecule consisting of two polypeptide chains. Tm molecules are bound head to tail forming a polymer that runs over the actin subunits. Aditionally, Tm bind to actin and acts as a molecular barrier which blocks the myosin-binding sites on actin in relaxed muscle and prevents crossbridge cycling. In the presence of calcium ions, Tm changes formation and exposes myosin-binding sites.
Actin/Myosin Movie 2 [6]
Development of the neuromuscular junction
During week 9, i.e. beginning of the fetal period, the first neuromuscular junctions appear on the newly created myotubes (muscle fibers formed from the fusion of myoblasts into multi-nucleated fibers).[63]Formation of the neuromuscular junction during embryonic period is only partially understood. It is a multistep process requiring coordinated interactions between nerve terminals and muscle. The formation of a subsynaptic apparatus at the neuromuscular junction is an example of extreme subcellular differentiation induced by the motor neuron in a small segment of the muscle fiber. Four key components are involved in this process: agrin, MuSK, acetylcholine receptors and rapsyn.
- The growing end of motor neuron axons secret a protein called agrin.[64]
- MuSK is a receptor tyrosine kinase on muscle cell. Once activated by a signal protein (agrin in this case), the kinase domain of MuSK transfers a phosphate group from ATP to selected tyrosine side chains on itself. This process is called autophosphorylation.[65]
- Upon activation by agrin, MuSK signals via proteins (CK 2[66], Dok-7[67]and rapsyn) to induce clustering of acetocholine receptors (AChR).[68]
- Formation of clusters of AChR occur and are concentrated in the central regions of the myofibers.
- ACh released by branching nerve endings causes AChR-induced postsynaptic potentials that appear to determine endplate localization. Thus ACh regulates and refines the localization and stabilization of developing synaptic contacts.[69]
- The active ACh/AChR contact sites may prevent AChRs clustering in non-contacted regions.
- Motor axons branch onto specific regions (endplates) of individual muscle fibers.
The precise mechanisms that control AChR aggregation, guide ingrowing axons and contribute to correct synaptic patterning are unknown. A study proposed that the muscle AChR is central to this process. The following outlines this study and the original paper can be found here
Novel Mouse Model Reveals Distinct Activity-Dependent and –Independent Contributions to Synapse Development
During early embryonic period, AChRs are composed of α2βγδ subunits (AChRγ) and are replaced by adult AChRs composed of α2βεδ subunits (AChRε) during later embryonic stages and early postnatal development.[70]
Genetic mutation of genes coding for subunits of the AChR can greatly affect its activity. The mutation of ε subunit can reduce AChR's affinity for ACh. This mutation was used to generate γ/ε-fc mice, in which a mutated ε subunit cDNA fragment is fused into the γ subunit gene by homologous recombination to replace AChRγ with functionally "silent" receptors (AChRγ/ε-fc) during embryonic development. Mice diaphragms (a thin sheet of muscle under the lungs) were dissected and prepared for the study. [71]
The study findings show that AChRγ/ε-fc is expressed, clustered in endplate-like structures, and developmentally regulated like AChRγ in wild type (WT) mice. However, the lack of AChR-mediated activity leads to a series of synaptic abnormalities during embryonic development. [72]
The γ/ε-fc mice exhibit abnormal endplate distribution, axonal growth, muscle innervation, NMJ formation and distribution, as well as endplate morphology. Thus, the γ/ε-fc mouse line demonstrates the contribution of activity-dependent and -independent AChR-mediated processes to the formation of NMJs.
- Endplates distribution
In the images on the right, the endplates in γ/ε-fc diaphragms are spread out (B), not as centrally located as in WT diaphragms (A). Endplate band of γ/ε-fc diaphragm is more dispersed (C). The percentage of diaphragm witdth (%DW) occupied by endplate band in embryonic week 18 (E18) is reduced comparing to that in E16 in WT (p=0.022) (D). This is due to the lateral growth of myotubes without affecting endplate distribution. In γ/ε-fc diaphragm, there is no significant change (p>0.6) in %DW between E18 and E16. This implies that new endplates are continuously being formed in myotubes. [73]
Method: Endplates were imaged using a Zeiss Axioplan2 microscope, visualized with Alexa-488-labeled α-bungarotoxin.
- Innervation of individual endplates
The innervations pattern of γ/ε-fc diaphragms is disorganised where aberrantly located endplates attract nerves otherwise spreading directionless.
In WT diaphragms (A), nerve branches (green) terminate on endplates (red). In γ/ε-fc diaphragms (B), longer branches are formed to contact the wider spread out endplates and they continue to grow beyond the endplate, contacting additional endplates. Close-up of a single γ/ε-fc endplate (C) shows additional nerve sprouting after endplate innervations.
Method: Images of endplates were taken using a Leica TCS NT confocal microscope. Neurofilament and endplates are GFP- and r-bgt (red fluorescent AChR stain)-labeled.
- Presence of Multiple Endplates
Presumably, the effect of ACh prevents formation of additional NMJs on the same myofiber through unknown, possibly activity-regulated retrograde signals. If lack of activity impairs retrograde signalling, formation of multiple synapses on the same myofiber could be expected, i.e. the fiber could present several fully innervated endplates. Slow muscle fibers were used to test this hypothesis as they are present in smaller numbers than fast fibers in the developing diaphragm.
(A) and (B) are confocal images showing muscle fibers (blue) and endplates (green) in WT and γ/ε-fc mice respectively. Asterisks mark location of endplates on individual muscle fibers. The γ/ε-fc diaphragm presents multiple endplates on single muscle fibers (B). (C) illustrates a higher percentage of muscle fibers of γ/ε-fc embryo display more than one endplates per fiber when compared to WT embryo during different embryonic stage. (D) shows that average number of endplates per muscle fiber in E18 WT (1,12±0,03, white) and γ/ε-fc (1,95±0,07, gray) embryos (p<0,001).
Method: Muscle fibers are stained with anti-slow myosin antibody and endplates by Alexa488-labeled α-bungarotoxin. Confocal pictures were taken using a Leica TCS NT (Leica Microsystems) confocal microscope.
Common neuromuscular junction disorders
Neuromuscular junction disorders are due to impaired transmission of impulses at the neuromuscular junction. This may result from disorders that affect receptor function, pre- or postsynaptic membrane function, or acetylcholinesterase activity. The majority of diseases in this category are associated with autoimmune, toxic, or inherited conditions.
|Clinical Manifestation
|Myasthenia gravis
|Autoimmune neuromuscular disorder caused when antibodies block post-synaptic acetylcholine receptors in neuromuscular junctions. When the passage acetylcholine across the synapse is inhibited, muscles are unable to function normally and as a result they are quick to fatigue. [74]
|There are two forms of clinical manifestations of myasthenia gravis: ocular and generalized.In about 10-40% cases, weakness is restricted to the ocular muscles. The rest experience a fluctuating degree and variable combination of weakness in ocular, bulbar, limb, and respiratory muscles. Common symptoms include breathing difficulty, chewing or swallowing difficulty, fatigue, facial paralysis, double vision and eyelid drooping. [75]
|There is no cure, but long-term remission is possible. Some medications, such as neostigmine, improve the communication between the nerve and the muscle. Immunosuppressants may be used if symptoms are severe and other medications don't work well enough [76]
|Lambert–Eaton Myasthenic Syndrome (LEMS)
|Autoimmune, presynaptic disorder which involves impaired release of acetylcholine. [77] Symptoms include impaired proximal muscle function, eg hip and shoulder movement.
|Caused by antibody blockage voltage-gated calcium channels (VGCCs) in the presynaptic cell, resulting in decreased release of acetylcholine at the neuromuscular junction. Most occurrences follow cancer although LEMS may be diagnosed first. [78] Symptoms resemble those of Myasthenia gravis, most notably muscle weakness in limbs
|Azathioprene, steroids, and/or immunoglobin as immune system suppressants. Pyridostigmine, dyaminopyridine to enhance acetylcholine release. [79]
|A disease caused by the excrement of the bacteria Clostridium Botulinum. This excrement, known as Botulinum toxin, is an extremely lethal neurotoxin. It works by blocking the release of acetylcholine at neuromuscular junctions, resulting paralysis and ultimately respiratory failure. The bacteria may enter the body through wounds, or improperly canned or preserved food. [80]
Infant botulism occurs when living bacteria or its spores are eaten and grow within the baby's gastrointestinal tract. However, recently developed medical techniques use the toxin beneficially (botox). [81]
|Clinical manifestation of muscle weakness without fever is characteristic of botulism. It starts with facial muscles weakness, which then spreads to the arms and legs. Symptoms include diplopia or ptosis, dysphagia and dyspnoea. In addition, patients may experience dry mouth and GI related symptoms e.g. vomiting and constipation especially in infants. [82]
|For infants, Botulism Immune Globulin Intravenous-Human (BIG-IV) also known as BabyBIG. Antitoxins (Trivalent, Heptavalent) [83]
|Congenital myasthenic syndrome (CMS)
|Inherited disorder where not enough acetylcholine crosses the neuromuscular synapse with onset at or shortly after birth or in early childhood. [84]
|CMS can be pre-synaptic, where not enough acetycholine is produced or released in the first place, or post-synaptic, where acetylcholine receptors malfunction and do not stay open long enough. Symptoms are similar to those expressed through Myasthenia gravis. [85]
|Treatments vary depending on the type of CMS. Cholinesterase inhibitors, quinine, and fluoxetine are some effective clinical treatments. [86]
|Black widow spider venom
|The black widow spider produces a protein venom that causes a complete depletion of acetylcholine. [87] Local pain from the spider bite may be followed by severe muscle cramps, abdominal pain, weakness and tremors. In worse cases symptoms include nausea, vomiting, fainting, dizziness, chest pain, and respiratory difficulties [88]
|Alpha-latrotoxin causes the opening of cation channels in the presynaptic membrane. This channel opening causes increased release of neurotransmitters which over-stimulates motor endplates, causing pain, muscle cramps, tremors etc. [89]
|Most bites can be treated with opioid analgesics. Antivenom is usually only used in severe cases as it has a high incidence of allergic reactions. [90]
|Cobratoxins bind specifically to the acetylcholine receptor. [91]
|Cobratoxin causes paralysis by preventing the binding of acetylcholine to the nicotinic receptor (nicotinic acetylcholine receptor antagonist). Acetylcholine causes muscles to contract when activated, so when these receptors are blocked by cobratoxin, it results in muscle paralysis. [92]
|There seems to be no current cure for cobratoxin, but cobratoxin is controversially used as an analgesic due to its ability to block the connection between muscle and neuron. [93]
|Aminoglycosides and excess Magnesium
|These interfere with calcium-mediated release of quanta. Symptoms include nausea and vomiting, impaired breathing, hypotension, hypocalcemia, arrhythmia and asystole [94]
|Increased magnesium decreases impulse transmission across the neuromuscular junction. This results in loss of deep tendon reflexes, and muscle paralysis. Since this also affects smooth muscle function, excess magnesium can cause decreased or stopped respiration [95]
|Usually treatment is to simply stop the cause of the overdose. If severe symptoms are present, sometimes dialysis and an IV drip are required [96]
Current associated research
Analysis of neuromuscular development and function in C. elegans. Nicotine addiction occurs as a result of nicotinic neurotransmission, which plays a critical role in the vertebrate nervous system. Current studies work to identify the genes required for neurotransmission, such as acr-16 and cam-1. [97]
Muscle Mitochondrial Uncoupling Dismantles Neuromuscular Junction and Triggers Distal Degeneration of Motor Neurons (2009): Dupuis et al looked at abnormalities of the mitochondrial energy metabolism. Their findings proved that this defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases. Furthermore they suggested that muscle selective alterations in mitochondrial function might initiate NMJ pathology and participate in triggering motor neuron degeneration in ALS. Biochemical measurements were carried out followed by electromyography recordings and PCR analysis. [98]
Neurexin in Embryonic Drosophila Neuromuscular Junctions (2010): In this study, Chen et al unfolded the role of the neurexin in Drosophila glutamate receptor abundance. Their results suggested that neurexin in embryos is present both pre and postsynaptically. Presynaptic neurexin promotes presynaptic active zone formation and neurotransmitter release, but along with postsynaptic neurexin, also suppresses formation of ectopic glutamate receptor clusters. During the research several methods were used. Starting with the hybridization where embryos were manually staged and dissected to examine neurexin expression. Dissections were performed as for confocal imaging and electrophysiology. For electron microscopy, genotyped Drosophila eggs were dechorionated with bleach. [99]
TDP-43 Regulates Drosophila Neuromuscular Junctions Growth by Modulating Futsch/MAP1B levels and Synaptic Microtubules Organization (2010): Godena et al, unfolded that TDP-43 is an RNA binding protein and plays numerous roles in mRNA metabolism such us transcription, pre-mRNA splicing, mRNA stability, microRNA biogenesis, transport and translation. However, in pathological conditions such as ALS and FTLD, TDP-43 appears as a large insoluble protein aggregates which is redistributed within the cytoplasm. They concluded that the changes observed at the level of NMJs and synaptic boutons formation can be explained by defects at the cytoskeleton level. [100]
Future research
- Botulinum neurotoxin works at the neuromuscular junction, but many questions remain about the way it works. What proteins are involved in the transport the neurotoxin into the cholinergic nerve terminal? What factors control how long the toxin acts? New biotechnology has made further research feasible. Answers to these questions would restrict the toxin's appeal as a tool for bioterrorists and increase its effectiveness as a therapeautic agent for disorders of the neuromuscular junction. [7]
- Analysis of neuromuscular development and function in C. elegans. Future studies involving organisms such as C. elegans will identify the molecular machinery that is required for the development and function of the neuromuscular junction [101]
- Synaptic vesicle dynamics within neuromuscular junctions of synapto-phluorin expressing mice.Relationships between synaptic structure and function at the mammalian neuromuscular junction. Current experiments involving the expression of various genes such as synapto-pHlaurin (spH) in transgenic lines of mice reveal reasons for changes in synaptic strength and structure. These experiments lay the groundwork for future studies that will look into the processes underlying the plasticity of the nervous system. [102]
- Potential Application of Induced Pluripotent Stem Cells in Cell Replacement Therapy for Parkinson's Disease. Current research has shown that the use of embryonic stem cells to replace damaged tissue can be beneficial in various neurodegenerative diseases. These stem cells integrate and form connections with host cells. The problem with some stem cell treatments is the capability of these cells to form long axons from the spinal cord to the muscle cell and forming a junction with the muscle. Further research into the signaling mechanisms of the NMJ may find additional mechanisms by which transplanted cells may be of therapeutic benefit. [103]
External links
- Neuromuscular junction
- Excitation-contraction coupling
- Pubmed search for NMJ
- University of Dundee article on performing neurological examinations (Quadriceps "strongest")
- Microscopic stains of skeletal and cardiac muscular fibers to show striations. Note the differences in myofibrilar arrangements.
- acetylcholine (ACh): A chemical neurotransmitter in the brain and peripheral nervous system; the dominant neurotransmitter in the peripheral nervous system, released at neuromuscular junctions and synapses of the parasympathetic division.
- acetylcholinesterase (AChE): An enzyme found in the synaptic cleft, bound to the postsynaptic membrane, and in tissue fluids; breaks down and inactivates acetylcholine molecules.
- actin: The protein component of microfilaments that forms thin filaments in skeletal muscles and produces contractions of all muscles through interaction with thick (myosin) filaments
- action potential: A conducted change in the transmembrane potential of excitable cells, initiated by a change in the membrane permeability to sodium ions; see also nerve impulse.
- axon: The elongate extension of a neuron that conducts an action potential.
- axon hillock: In a multipolar neuron, the portion of the cell body adjacent to the initial segment.
- choline: A breakdown product or precursor of acetylcholine.
- cholinergic synapse: A synapse where the presynaptic membrane releases acetylcholine on stimulation.
- cholinesterase: The enzyme that breaks down and inactivates acetylcholine.
- depolarization: A change in the transmembrane potential from a negative value toward 0 mV.
- electrical coupling: A connection between adjacent cells that permits the movement of ions and the transfer of graded or conducted changes in the transmembrane potential from cell to cell.
- gap junctions: Connections between cells that permit electrical coupling.
- innervation: The distribution of sensory and motor nerves to a specific region or organ.
- ion: An atom or molecule bearing a positive or negative charge due to the donation or acceptance, respectively, of an electron.
- ionotrophic receptors in the NMJ are receptors that allow ions to pass through them when they bind to acetylcholine
- muscarinic receptors: Membrane receptors sensitive to acetylcholine and to muscarine, a toxin produced by certain mushrooms; located at all parasympathetic neuromuscular and neuroglandular junctions and at a few sympathetic neuromuscular and neuroglandular junctions.
- myasthenia gravis: A muscular weakness due to a reduction in the number of acetylcholine receptor sites on the sarcolemmal surface; suspected to be an autoimmune disorder.
- myoblast: A type of embryonic progenitor cell that gives rise to a muscle cell
- myofiber: Another name for muscle fiber
- nerve impulse: An action potential in a neuron cell membrane.
- neurofilaments: Microfilaments in the cytoplasm of a neuron.
- neuromuscular junction: A synapse between a neuron and a muscle cell.
- nicotinic receptors: Acetylcholine receptors on the surfaces of sympathetic and parasympathetic ganglion cells; respond to the compound nicotine.
- peripheral nervous system (PNS): All neural tissue outside the central nervous system.
- rapsyn: A peripheral membrane component required for the aggregation of the AChRs in the muscle membrane.
- repolarization: The movement of the transmembrane potential away from a positive value and toward the resting potential.
- resting potential: The transmembrane potential of a normal cell under homeostatic conditions.
- sarcolemma: The cell membrane of a muscle cell.
- sarcomere: The smallest contractile unit of a striated muscle cell.
- sarcoplasm: The cytoplasm of a muscle cell.
- signal Transduction is the process by which an extracellular signaling molecule activates a membrane receptor that in turn alters intracellular molecules creating a response
- sliding filament theory: The concept that a sarcomere shortens as the thick and thin filaments slide past one another.
- synapse: The site of communication between a nerve cell and some other cell; if the other cell is not a neuron, the term neuromuscular or neuroglandular junction is often used.
- thick filament: A cytoskeletal filament in a skeletal or cardiac muscle cell; composed of myosin, with a core of titin.
- thin filament: A cytoskeletal filament in a skeletal or cardiac muscle cell; consists of actin, troponin, and tropomyosin.
- threshold: The transmembrane potential at which an action potential begins.
- tropomyosin: A protein on thin filaments that covers the active sites in the absence of free calcium ions.
- troponin: A protein on thin filaments that binds to tropomyosin and to G actin.
- ↑ Farrugia M.E. 2002, "Myasthenia Gravis", JR Coll Physicians Edinb, vol 34, pp. 14-18.
- ↑ Leake, C. D. An Historical Account of Pharmacology to the Twentieth Century; Charles C. Thomas: Springfield, IL, 1975.
- ↑ Sneader, W. Drug Discovery: The Evolution of Modern Medicines; Wiley: New York, 1985
- ↑ Feldberg WS. Henry Hallett Dale, 1875-1968. Biogr Mem Fellows R Soc. 1970;16:77–174.
- ↑ Dale HH, Feldberg W, Vogt M. 1936. Release of acetylcholine at voluntary motor nerve endings. J. Physiol. 86:353–80
- ↑ Hodgkin, Alan. Chance & design: reminiscences of science in peace and war (p.324)
- ↑ Fatt P & Katz B (1951). An analysis of the end-plate potential recorded with an intra-cellular electrode. J Physiol 115, 320–370
- ↑ del Castillo J & Katz B (1954). Quantal components of the end-plate potential. J Physiol 124, 560–573
- ↑ Katz B. 1966. Nerve, Muscle and Synapse. New York: McGraw-Hill
- ↑ Sanes JR, Marshall LM, McMahan UJ. 1978. Reinnervation of muscle fiber basal lamina after removal of myofibers. Differentiation of regenerating axons at original synaptic sites. J. Cell Biol. 78:176–98
- ↑ Dennis MJ. 1981. Development of the neuromuscular junction: inductive interactions between cells. Annu. Rev. Neurosci. 4:43–68
- ↑ Anderson MJ. Nerve-induced remodeling of muscle basal lamina during synaptogenesis. J Cell Biol. 1986 Mar;102(3):863-77. PubMed PMID: 3005339; PubMed Central PMCID: PMC2114107.
- ↑ McMahan, U.J. 1990. The agrin hypothesis. Cold Spring Harb. Symp. Quant. Biol. 55:407–418
- ↑ Lewis, P., et al. Muscle & Nerve. Published in May 2000.
- ↑ Thesleff S. Transmitter release in botulinum-poisoned muscles. J Physiol (Paris). 1984;79(4):192-5. Review. PubMed PMID: 6152289.
- ↑ Kurshan PT, Oztan A, Schwarz TL. Presynaptic alpha2delta-3 is required for synaptic morphogenesis independent of its Ca2+-channel functions. Nat Neurosci. 2009 Nov;12(11):1415-23. Epub 2009 Oct 11. PubMed PMID: 19820706; PubMed Central PMCID: PMC2996863.
- ↑ Katz B, Miledi R. The role of calcium in neuromuscular facilitation. J Physiol. 1968 Mar;195(2):481-92. PubMed PMID: 4296699; PubMed Central PMCID: PMC1351674.
- ↑ Hirose S, Vieth WR. Transport of acetylcholine in a membrane. Laminate model of the neuromuscular junction. Appl Biochem Biotechnol. 1984 Feb;9(1):81-93. PubMed PMID: 6476821.
- ↑ Birks RI, Burstyn PG, Firth DR. The form of sodium-calcium competition at the frog myoneural junction. J Gen Physiol. 1968 Dec;52(6):887-907. PubMed PMID: 4301843; PubMed Central PMCID: PMC2225848.
- ↑ Hirose S, Vieth WR. Transport of acetylcholine in a membrane. Laminate model of the neuromuscular junction. Appl Biochem Biotechnol. 1984 Feb;9(1):81-93. PubMed PMID: 6476821.
- ↑ Hirose S, Vieth WR. Transport of acetylcholine in a membrane. Laminate model of the neuromuscular junction. Appl Biochem Biotechnol. 1984 Feb;9(1):81-93. PubMed PMID: 6476821.
- ↑ Birks RI, Burstyn PG, Firth DR. The form of sodium-calcium competition at the frog myoneural junction. J Gen Physiol. 1968 Dec;52(6):887-907. PubMed PMID: 4301843; PubMed Central PMCID: PMC2225848.
- ↑ Walke W, Staple J, Adams L, Gnegy M, Chahine K, Goldman D. Calcium-dependent regulation of rat and chick muscle nicotinic acetylcholine receptor (nAChR) gene expression. J Biol Chem. 1994 Jul 29;269(30):19447-56. PubMed PMID: 8034713.
- ↑ 1: Birks RI, Burstyn PG, Firth DR. The form of sodium-calcium competition at the frog myoneural junction. J Gen Physiol. 1968 Dec;52(6):887-907. PubMed PMID: 4301843; PubMed Central PMCID: PMC2225848.
- ↑ Walke W, Staple J, Adams L, Gnegy M, Chahine K, Goldman D. Calcium-dependent regulation of rat and chick muscle nicotinic acetylcholine receptor (nAChR) gene expression. J Biol Chem. 1994 Jul 29;269(30):19447-56. PubMed PMID: 8034713.
- ↑ Walke W, Staple J, Adams L, Gnegy M, Chahine K, Goldman D. Calcium-dependent regulation of rat and chick muscle nicotinic acetylcholine receptor (nAChR) gene expression. J Biol Chem. 1994 Jul 29;269(30):19447-56. PubMed PMID: 8034713.
- ↑ Hirose S, Vieth WR. Transport of acetylcholine in a membrane. Laminate model of the neuromuscular junction. Appl Biochem Biotechnol. 1984 Feb;9(1):81-93. PubMed PMID: 6476821.
- ↑ Birks RI, Burstyn PG, Firth DR. The form of sodium-calcium competition at the frog myoneural junction. J Gen Physiol. 1968 Dec;52(6):887-907. PubMed PMID: 4301843; PubMed Central PMCID: PMC2225848.
- ↑ Walke W, Staple J, Adams L, Gnegy M, Chahine K, Goldman D. Calcium-dependent regulation of rat and chick muscle nicotinic acetylcholine receptor (nAChR) gene expression. J Biol Chem. 1994 Jul 29;269(30):19447-56. PubMed PMID: 8034713.
- ↑ Wu H, Xiong WC, Mei L. To build a synapse: signaling pathways in neuromuscular junction assembly. Development. 2010 Apr;137(7):1017-33. Review. PubMed PMID: 20215342; PubMed Central PMCID: PMC2835321.
- ↑ Pappas GD, Peterson ER, Masurovsky EB, Crain SM. Electron microscopy of the in vitro development of mammalian motor end plates. Ann N Y Acad Sci. 1971 Sep 15;183:33-45. PubMed PMID: 4107829.
- ↑ Walke W, Staple J, Adams L, Gnegy M, Chahine K, Goldman D. Calcium-dependent regulation of rat and chick muscle nicotinic acetylcholine receptor (nAChR) gene expression. J Biol Chem. 1994 Jul 29;269(30):19447-56. PubMed PMID: 8034713.
- ↑ Pappas GD, Peterson ER, Masurovsky EB, Crain SM. Electron microscopy of the in vitro development of mammalian motor end plates. Ann N Y Acad Sci. 1971 Sep 15;183:33-45. PubMed PMID: 4107829.
- ↑ [1]
- ↑ [2]
- ↑ Imeri L, Opp MR. How (and why) the immune system makes us sleep. Nat Rev Neurosci. 2009 Mar;10(3):199-210. Epub 2009 Feb 11. Review. PubMed PMID: 19209176; PubMed Central PMCID: PMC2839418.
- ↑ Elmqvist D, Feldman DS. Influence of ionic environment on acetylcholine release from the motor nerve terminals. Acta Physiol Scand. 1966 May;67(1):34-42. PubMed PMID: 5963300.
- ↑ Morisot P. [Physiology of the motor plate]. Anesth Analg (Paris). 1966 Apr-Jun;23(2):459-70. Review. French. PubMed PMID: 5327039.
- ↑ Levine L. An electrophysiological study of chelonian skeletal muscle. J Physiol. 1966 Apr;183(3):683-713. PubMed PMID: 5919565; PubMed Central PMCID: PMC1357516.
- ↑ Elmqvist D, Feldman DS. Influence of ionic environment on acetylcholine release from the motor nerve terminals. Acta Physiol Scand. 1966 May;67(1):34-42. PubMed PMID: 5963300.
- ↑ Morisot P. [Physiology of the motor plate]. Anesth Analg (Paris). 1966 Apr-Jun;23(2):459-70. Review. French. PubMed PMID: 5327039.
- ↑ Imeri L, Opp MR. How (and why) the immune system makes us sleep. Nat Rev Neurosci. 2009 Mar;10(3):199-210. Epub 2009 Feb 11. Review. PubMed PMID: 19209176; PubMed Central PMCID: PMC2839418.
- ↑ Levine L. An electrophysiological study of chelonian skeletal muscle. J Physiol. 1966 Apr;183(3):683-713. PubMed PMID: 5919565; PubMed Central PMCID: PMC1357516.
- ↑ Lindstrom J. Nicotinic acetylcholine receptors in health and disease. Mol Neurobiol. 1997 Oct;15(2):193-222. Review. PubMed PMID: 9396010.
- ↑ Guyton AC, Hall JE: Textbook of Medical Physiology (2006) Elsevier Saunders, Philadelphia. P.87
- ↑ Guyton AC, Hall JE: Textbook of Medical Physiology (2006) Elsevier Saunders, Philadelphia. P.87
- ↑ Kelly AM, Zacks SI. The fine structure of motor endplate morphogenesis. J Cell Biol. 1969 Jul;42(1):154-69. PubMed PMID: 5786980; PubMed Central PMCID: PMC2107582.
- ↑ Junqueira C.L. & Caraneiro J., 2005. Basic Histology, text & atlas, 11th edition. McGraw-Hill Companies.
- ↑ Ogata T, Murata F. Fine structure of motor endplate in red, white and intermediate fibers of mammalian fast muscle. Tohoku J Exp Med. 1969 Jun;98(2):107-15. PubMed PMID: 5811099.
- ↑ Pye RJ, Greaves MW. Benign rheumatoid nodules of the skin. Br J Dermatol. 1979 Jul;101 Suppl 17:58-9. PubMed PMID: 465342.
- ↑ Buckley GA. The structure and development of the motor end-plate. Physiotherapy. 1972 Aug;58(8):274-6. PubMed PMID: 4669373.
- ↑ 1: Rusakov DA, Savtchenko LP, Zheng K, Henley JM. Shaping the synaptic signal: molecular mobility inside and outside the cleft. Trends Neurosci. 2011 Apr 4. [Epub ahead of print] PubMed PMID: 21470699.
- ↑ 1: Rees RP. The morphology of interneuronal synaptogenesis: a review. Fed Proc. 1978 May 15;37(7):2000-9. Review. PubMed PMID: 205437.
- ↑ 1: Vrbová G, Wareham AC. Effects of nerve activity on the postsynaptic membrane of skeletal muscle. Brain Res. 1976 Dec 24;118(3):371-82. PubMed PMID: 1009425.
- ↑ Herrera AA, Grinnell AD, Wolowske B. Ultrastructural correlates of naturally occurring differences in transmitter release efficacy in frog motor nerve terminals. J Neurocytol. 1985 Apr;14(2):193-202. PubMed PMID: 2864400.
- ↑ Sausville EA, Trepel JB, Moyer JD. Inhibitors of bombesin-stimulated intracellular signals: interruption of an autocrine pathway as a therapeutic strategy in small cell lung carcinoma. Prog Clin Biol Res. 1990;354A:193-207. PubMed PMID: 2174173.
- ↑ Dr. med. H. Jastrow, Dept. of Anatomy and Cell Biology, Johannes Gutenberg University, 55099 Mainz, Germany
- ↑ Stephen G. Lipson, Ariel Lipson, Henry Lipson, Optical Physics 4th Edition, Cambridge University Press, ISBN 9780521493451
- ↑ O1 Optical Microscopy By Katarina Logg. Chalmers Dept. Applied Physics. 2006-01-20
- ↑ Erni R, Rossell MD, Kisielowski C, Dahmen U. Atomic-resolution imaging with a sub-50-pm electron probe. Phys Rev Lett. 2009 Mar 6;102(9):096101. Epub 2009 Mar 2. PubMed PMID: 19392535.
- ↑ Saint DA, McLarnon JG, Quastel DM. Anion permeability of motor nerve terminals. Pflugers Arch. 1987 Jul;409(3):258-64. PubMed PMID: 3627946.
- ↑ Drummy LF, Yang J, Martin DC. Low-voltage electron microscopy of polymer and organic molecular thin films. Ultramicroscopy. 2004 Jun;99(4):247-56. PubMed PMID: 15149719.
- ↑ Wu H, Xiong WC, Mei L. To build a synapse: signaling pathways in neuromuscular junction assembly. Development. 2010 Apr;137(7):1017-33. Review. PubMed PMID: 20215342; PubMed Central PMCID: PMC2835321.
- ↑ Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD. Agrin acts via a MuSK receptor complex. Cell. 1996 May 17;85(4):513-23. PubMed PMID: 8653787
- ↑ DeChiara TM, Bowen DC, Valenzuela DM, Simmons MV, Poueymirou WT, Thomas S, Kinetz E, Compton DL, Rojas E, Park JS, Smith C, DiStefano PS, Glass DJ, Burden SJ, Yancopoulos GD. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell. 1996 May 17;85(4):501-12. PubMed PMID: 8653786.
- ↑ Nierenberg AA. The medical consequences of the selection of an antidepressant. J Clin Psychiatry. 1992 Sep;53 Suppl:19-24. Review. PubMed PMID: 1522076.
- ↑ Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006 Jun 23;312(5781):1802-5. PubMed PMID: 16794080.
- ↑ Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD. Agrin acts via a MuSK receptor complex. Cell. 1996 May 17;85(4):513-23. PubMed PMID: 8653787
- ↑ Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD. Agrin acts via a MuSK receptor complex. Cell. 1996 May 17;85(4):513-23. PubMed PMID: 8653787.
- ↑ Pacifici PG, Peter C, Yampolsky P, Koenen M, McArdle JJ, Witzemann V. Novel mouse model reveals distinct activity-dependent and -independent contributions to synapse development. PLoS One. 2011 Jan 31;6(1):e16469. PubMed PMID: 21305030; PubMed Central PMCID: PMC3031568.
- ↑ Pacifici PG, Peter C, Yampolsky P, Koenen M, McArdle JJ, Witzemann V. Novel mouse model reveals distinct activity-dependent and -independent contributions to synapse development. PLoS One. 2011 Jan 31;6(1):e16469. PubMed PMID: 21305030; PubMed Central PMCID: PMC3031568.
- ↑ Pacifici PG, Peter C, Yampolsky P, Koenen M, McArdle JJ, Witzemann V. Novel mouse model reveals distinct activity-dependent and -independent contributions to synapse development. PLoS One. 2011 Jan 31;6(1):e16469. PubMed PMID: 21305030; PubMed Central PMCID: PMC3031568.
- ↑ Pacifici PG, Peter C, Yampolsky P, Koenen M, McArdle JJ, Witzemann V. Novel mouse model reveals distinct activity-dependent and -independent contributions to synapse development. PLoS One. 2011 Jan 31;6(1):e16469. PubMed PMID: 21305030; PubMed Central PMCID: PMC3031568.
- ↑ McGrogan A, Sneddon S, de Vries CS. The incidence of myasthenia gravis: a systematic literature review. Neuroepidemiology. 2010;34(3):171-83. Epub 2010 Feb 2. Review. PubMed PMID: 20130418.
- ↑ Losen M, Stassen MH, Martínez-Martínez P, Machiels BM, Duimel H, Frederik P, Veldman H, Wokke JH, Spaans F, Vincent A, De Baets MH. Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis. Brain. 2005 Oct;128(Pt 10):2327-37. Epub 2005 Sep 8. PubMed PMID: 16150851.
- ↑ Losen M, Martínez-Martínez P, Phernambucq M, Schuurman J, Parren PW, De Baets MH. Treatment of myasthenia gravis by preventing acetylcholine receptor modulation. Ann N Y Acad Sci. 2008;1132:174-9. PubMed PMID: 18567867.
- ↑ Mareska M, Gutmann L. Lambert-Eaton myasthenic syndrome. Semin Neurol. 2004 Jun;24(2):149-53. Review. PubMed PMID: 15257511.
- ↑ Verschuuren JJ, Wirtz PW, Titulaer MJ, Willems LN, van Gerven J. Available treatment options for the management of Lambert-Eaton myasthenic syndrome. Expert Opin Pharmacother. 2006 Jul;7(10):1323-36. Review. PubMed PMID: 16805718.
- ↑ Rees JH. Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage. J Neurol Neurosurg Psychiatry. 2004 Jun;75 Suppl 2:ii43-50. PubMed PMID: 15146039; PubMed Central PMCID: PMC1765657.
- ↑ Agarwal AK, Goel A, Kohli A, Rohtagi A, Kumar R. Food-borne botulism. J Assoc Physicians India. 2004 Aug;52:677-8. PubMed PMID: 15847370.
- ↑ Aoki KR. Botulinum toxin: a successful therapeutic protein. Curr Med Chem. 2004 Dec;11(23):3085-92. Review. PubMed PMID: 15579002.
- ↑ Glik D, Harrison K, Davoudi M, Riopelle D. Public perceptions and risk communications for botulism. Biosecur Bioterror. 2004;2(3):216-23. PubMed PMID: 15588060.
- ↑ Bossi P, Tegnell A, Baka A, van Loock F, Hendriks J, Werner A, Maidhof H, Gouvras G; Task Force on Biological and Chemical Agent Threats, Public Health Directorate, European Commission, Luxembourg. Bichat guidelines for the clinical management of botulism and bioterrorism-related botulism. Euro Surveill. 2004 Dec 15;9(12):E13-4. PubMed PMID: 15677843.
- ↑ Hantaï D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Curr Opin Neurol. 2004 Oct;17(5):539-51. Review. PubMed PMID: 15367858.
- ↑ Eymard B, Ioos C, Barois A, Estournet B, Mayer M, Fournier E, Yasaki E, Prioleau C, Bauché S, Gaudon K, Leroy JP, Koenig J, Richard P, Hantaï D. [Congenital myasthenic syndromes due to mutations in the rapsyn gene]. Rev Neurol (Paris). 2004 May;160(5 Pt 2):S78-84. Review. French. PubMed PMID: 15269664.
- ↑ Farrugia ME. Myasthenic syndromes. J R Coll Physicians Edinb. 2011 Mar;41(1):43-7; quiz 48. PubMed PMID: 21365067.
- ↑ Martin, Louise (1988). Black Widow Spiders. Rourke Enterprises, Inc.. pp. 18–20.
- ↑ Preston-Malfham, Ken (1998). Spiders. Edison, New Jersey: Chartwell Books. p. 40.
- ↑ Insects and Spiders. New York: St. Remy Media Inc. / Discovery Books. 2000. p. 35.
- ↑ Martin, Louise (1988). Black Widow Spiders. Rourke Enterprises, Inc.. pp. 18–20.
- ↑ YANG CC. CRYSTALLIZATION AND PROPERTIES OF COBROTOXIN FROM FORMOSAN COBRA VENOM. J Biol Chem. 1965 Apr;240:1616-8. PubMed PMID: 14285499.
- ↑ Konstantakaki M, Changeux JP, Taly A. Docking of alpha-cobratoxin suggests a basal conformation of the nicotinic receptor. Biochem Biophys Res Commun. 2007 Aug 3;359(3):413-8. Epub 2007 Jun 4. PubMed PMID: 17555709.
- ↑ Hue B, Buckingham SD, Buckingham D, Sattelle DB. Actions of snake neurotoxins on an insect nicotinic cholinergic synapse. Invert Neurosci. 2007 Sep;7(3):173-8. Epub 2007 Aug 21. PubMed PMID: 17710455.
- ↑ Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet. 1955; 100:131–140
- ↑ Lu JF,Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia. Clin Pharmacokinet. 2000; 38:305–314
- ↑ Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet. 1955; 100:131–140
- ↑ Analysis of neuromuscular development and function in C. elegans [3] Accessed 8 May 2011.
- ↑ Dupuis L, Gonzalez de Aguilar JL, Echaniz-Laguna A, Eschbach J, Rene F, Oudart H, Halter B, Huze C, Schaeffer L, Bouillaud F, Loeffler JP. Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. PLoS One. 2009;4(4):e5390. Epub 2009 Apr 30. PubMed PMID: 19404401; PubMed Central PMCID: PMC2671839.
- ↑ Chen K, Gracheva EO, Yu SC, Sheng Q, Richmond J, Featherstone DE. Neurexin in embryonic Drosophila neuromuscular junctions. PLoS One. 2010 Jun 14;5(6):e11115. PubMed PMID: 20559439; PubMed Central PMCID: PMC2885429.
- ↑ Godena VK, Romano G, Romano M, Appocher C, Klima R, Buratti E, Baralle FE, Feiguin F. TDP-43 regulates Drosophila neuromuscular junctions growth by modulating Futsch/MAP1B levels and synaptic microtubules organization. PLoS One. 2011 Mar 11;6(3):e17808. PubMed PMID: 21412434; PubMed Central PMCID: PMC3055892.
- ↑ Analysis of neuromuscular development and function in C. elegans [4] Accessed 8 May 2011.
- ↑ Synaptic vesicle dynamics within neuromuscular junctions of synapto-phluorin expressing mice. [5] Accessed 8 May 2011
- ↑ Stem cell-derived neurotrophic support for the neuromuscular junction in spinal muscular atrophy PMID20955113
Coordinator Comment to all Groups
I will add a general comment that will be the same to all groups under this heading.
Referencing Extension Problem
--Mark Hill 13:16, 3 May 2011 (EST) As mentioned in the lecture, I am aware of the referencing extension problem on your project pages. I have the following temporary solution, of removing the extension, so that groups can continue to add content to their project pages. I am also giving everyone a 1 week extension before the peer assessment.
This should only be done if your project page is not allowing you to save changes!
A. The Easy Way....
The following 4 steps can be done on the webpage or select all content in edit mode, copy and paste into a text editor. All steps must be completed before you attempt to save.
- In page edit mode, find all <pubmed> reference tags.
- Replace this tag with [http://www.ncbi.nlm.nih.gov/pubmed/ Note, there should be no spaces between the internet address and the pmid number.
- Now find all </pubmed> reference tags.
- Replace this second tag with ]
This will generate a numbered reference list that we can later fix up.
B. The Better Looking Result....
Whatever is between the <ref> </ref></pubmed> tags is what will appear in your reference list, so you can format the reference and link to appear in your reference list.
|2011 Projects: Synaptic Junctions | Gap Junctions | Tight Junctions | Desmosomes | Adherens Junctions | Neuromuscular Junction


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Floral Fantasy set/2 cup & saucer khaki
Out of stock
Part of the Floral Fantasy Bloomingtales set, these cups & saucers will be an exquisite addition to your dinnerware.
- The set is delivered in a gift box
- Floral Fantasy is all about big Asian flowers combined with small stylized elements, making a positive big impression on your guests.
- Material: 100% porcelain
- Please wash by hand. It's not safe to use this in a dishwasher or microwave.
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Our Lady of Altotting
Shrine located in Altotting, Bavaria, Germany, the octagonal chapel was constructed of native stone c.680 and survives today. Wars and pestilence and politics have caused the area to change hands several times, but the chapel has always survived. The small image of Our Lady was carved of lime wood c.1330, its surface blackened by age, the uncounted thousands of candles burned near it, and a fire in 907 that threatened to destroy it.
In 1489 a drowned child returned to life after being prayerfully placed before a this image of Mary. Many miracles and cures have since been attributed to Our Lady of Altotting intercession, and the area is known as the "Lourdes of Germany".
The small chapel has been a site for pilgrimage for over 500 years. Saint Conrad of Parzham served as chapel doorkeeper for over 30 years, and Pope John Paul II visited in 1980. It is one of the richest shrines in Europe with a immense store of treasure donated by pilgrims through the centuries; these items are not on display, but the crutches and other evidence of healings are there for all to see.
- "Our Lady of Altotting". CatholicSaints.Info. 19 November 2016. Web. 25 September 2020. <>


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Meatloaf is fairly hard to take pictures of that do it justice. This is the best meatloaf, ever. Take my word for it.
Alex and I decided we are going to continue eating healthy but eat meat once in a while, and started off with this meatloaf, since this was on Sunday, before I'd gotten my stitches out and wasn't sure if I should be eating solid food. Don't worry, I'm not going to suggest you put this in the blender at the end of the post. I asked Alex to make this since I was working later than him, and he followed the recipe that I had ripped out of a magazine a while ago. This is from America's Test Kitchen's Magazine, Cooks Country.
2/3 c gf breadcrumbs (toasted then crushed Udi's bread ends is what we use)
1/3 c milk
1 lb ground beef
1 lb fresh chicken or pork sausages (we used Italian and hot), removed from the casing
2 egg yolks
2 t mustard (we used spicy)
1/2 t dried thyme
salt and pepper
Line a cookie sheet with foil and lightly grease. Heat oil and cook onions until softened and lightly browned, then add garlic and cook until fragrant. Set aside. Process the breadcrumbs and milk in the food processor until smooth, then add beef and sausage and pulse until combined. Transfer to a bowl, add onions, eggs, mustard, thyme and 1 t salt and 3/4 t pepper, and mix with your hands until combined. Important! take off your rings that have stone settings before mixing meat with your hands!
Preheat your broiler, and lump your meat into a wide, flat loaf. Broil for about 5 minutes until well browned. Brush 2 T of the reserved 1/4 c glaze onto the loaf, then broil again for about 2 minutes, until browned further. Turn the heat down to 350 and brush the rest of the 1/4 c glaze onto the loaf. Bake 40-45 minutes (we cooked ours 42), then remove from oven and tent with foil, letting rest for 20 minutes. Serve with the rest of the glaze to your swooning wife.


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'Monster from the deep' stops to play on rare visit to Coast
IT'S a whale. No, it's a shark.
Actually, it's the world's biggest fish.
A whale shark, rarely seen off Sunshine Coast waters, spent 40 minutes playing with eight lucky tourists diving with Dive Noosa on Saturday.
Business owner Brett Bell said he didn't believe it when one of the divers he was with on Jew Shoal reef said they spotted a whale shark.
"Then this massive shape went under the boat," Mr Bell said.
"Everyone jumped in and snorkelled for 40 minutes. The whale shark just kept cruising around and coming back to us, coming up to the boat.
"It swam straight up to me at one point, it was just phenomenal."
Mr Bell said he had never had a whale shark approach him in his five years with the business.
"I've only heard of a whale shark being in Laguna Bay just once in the past 12 years," he said.


text:
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Retina Laptop Mockup
Super High Quality Mockup for your presentations for Apps, Website Templates and other Artworks…Each Group is organized into layers so you can double click on LCD layer and paste your artworks, it's very easy, you can customize the color of background too. the great minimal way to present your works for your clients or your website. There is a Loop included you can simply move it around and it Automatically Magnifying the Screen. it's great to show details on your artworks.


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1/4 oz 2017 South Korean Tiger Gold Round
We'll assure you the lowest price on the web, when you order your ¼ oz 2017 South Korean Tiger gold round from our online store today. This exquisite series saw inception in 2016 and features immaculate artistic renderings of one of the world's most endangered big cat species, the Korean or Siberian Tiger.
The coin's obverse features a marvellously detailed rendering of a Korean Tiger roaring. Also included on the obverse, the weight, date of issue and 'Korean Tiger' title.
On the reverse of the coin is a typographical relief, made of letters of the Korean alphabet, arranged in the shape of the Korean map. The map is flanked by KOMSCO's latent security feature and Korea's national emblem, while the Korean legend and the coin's metal content and 9999 purity appear within the wide border on the reverse side, which is decorated with a design of tiger stripes.
Sadly, the bamboo forests of Korea are no longer home to this majestic predator, as the last Korean Tiger was hunted there in 1922; only 400 of the species remain, in the far eastern parts of Russia and Siberia. Remember the Korean Tiger in his prime and diversify your holdings with a ¼ oz 2017 South Korean Tiger gold round today.
The coin will come in a display box with a certificate of authenticity.
|South Korea
|Brilliant uncirculated
|A close up of a tiger roaring, as well as the year, title, and troy ounce weight of the round.
|Letters of the Korean alphabet, arranged in the shape of the Korean map.


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I haven't used this service yet but it certainly looks promising. GedTree.com creates beautiful genealogy charts, suitable for framing. The information is obtained from YOUR GEDCOM file.
Click on the above image to view a larger version.
NOTE: A GEDCOM file is a file of genealogy information created by your favorite genealogy program. For an explanation of GEDCOM files, see my earlier article, GEDCOM Explained, at https://blog.eogn.com/2014/05/24/gedcom-explained.
Once the file has been uploaded, you can then select anyone in that file as the "home person" and then choose from a variety of printed designs. The system will then produce your custom family tree print. Typical examples might include "all the known ancestors of the home person" or "All the descendants of the home person."
Click on the above image to view a larger version.
You can review the print online to check for any errors or to make modifications. You also have the option to choose how you'd like missing names and dates to be formatted. You might want to experiment with several of the available designs. Once you have finalized the design, you can save it to GedTree.com and then make an online payment. Your custom wall chart, suitable for framing, will then be printed on GedTree.com's large color printers and will be mailed to you.
Click on the above image to view a larger version.
A few of the available designs are shown in this article but more designs and more information may be found at http://www.GedTree.com.


text: Welcome! The UC Department of Dermatology comprises of a multi-site dermatologic general and subspecialty practice, two affiliated but independent patient care entities. In addition, the department is home to three faculty research laboratories and a university-based administrative unit. We invite you to learn more about: Our History Research Efforts Clinical Care via UC Health


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Active UNDELETE Lite 8.5.19
Free undelete software Active UNDELETE Lite Freeware is powerful data recovery software that helps you to recover lost, deleted and formatted data from Hard Drives, USB Disks, Dynamic Volumes, Hardware or Software RAIDs.
With Active UNDELETE Lite Freeware you can recover deleted files and folders, detect deleted partitions and recover data from them, perform an Advanced Scan of physical disk and organize the result using Scan Result View, preview files before restoring. It supports HDD's larger then 2TB, supports file systems: NTFS, FAT, FAT32, exFAT, HFS+, Ext2/Ext3/Ext4, UFS. Active UNDELETE Lite Freeware supports recovery from Removable Drives and digital media like Secure Digital, CompactFlash, SmartMedia, MemoryStick. For advanced features, such us recovery data from RAID's, restoring partitions, low level disk editing and much more please evaluate Professional edition.


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Robidas Making Great Progress, but Will be Patient With Returnby Mark Stepneski / Dallas Stars
Defenseman Stephane Robidas hasn't been wearing the red no-contact jersey as the Dallas Stars resumed practices following the Olympic break, but that doesn't mean he is close to returning from the broken leg he suffered in late November. He's made a lot of progress in his recovery, but he still has a ways to go before he can play.
"He's not ready for physical play," said Stars assistant coach James Patrick. "His skating has gotten better and better, and he's way ahead of schedule. I don't know what his timetable is, but I think he is still weeks away."
When Robidas broke the leg in a game against Chicago on November 29, the timetable for his return was four to six months. Four months from the time of the injury would be late March. That he's practicing, and was on the ice for a couple of practices before the Stars headed off on the Olympic break, is impressive and why he appears to be ahead of schedule.
"I am very happy. I didn't expect to be back before the break, having two practices before the break. I think that was a big step for me mentally," Robidas said. "I was pretty happy with it, even though I am not 100 percent. The last couple practices I've been able to go through every drill. Guys are taking it pretty easy on me, but just to be back in that groove, it's been really good."
Robidas broke both his tibia and fibula when his skate got caught in a rut in that game against the Blackhawks. He had surgery the following morning. It's been a long road to get where he is now, and there is still more work to be done.
"Conditioning is pretty good, but every time I have to stop and start again, it's the pounding," Robidas said. "If I glide and skate with the flow, I am fine. But the push – it's my strong leg – so when I go to start it's always on that leg. I'd like to push on the other one because it is stronger, but I've always been doing that."
Robidas said he'll try not to push things, try to read how he feels and listen to the doctors and trainers. He'll see how practices go in the near future to see if he is ready to ramp up the physical side of things.
"The doctor told me I have to read it and get into it slowly. He said the leg is pretty good right now, it's pretty strong," Robidas said. "The callus was forming around the bone and it's pretty strong right now, but he doesn't want me to push through something where I have pain. He said I've got to listen to my body, so that's what I'll do in the next couple weeks. … I can play with pain, but mentally I've got to be able to do what I need to do and not be thinking about whether I can do something. It's a fast game out there."
Prior to the break there was talk of Robidas possibly returning by the middle of March, a couple weeks earlier than expected. For now, Robidas said he doesn't want to set a timetable. He watched Tampa Bay's Steven Stamkos, who is trying to comeback from a broken leg, set a return date and then be disappointed when he couldn't meet it.
"I don't want to set a goal," Robidas said. "I saw what Stamkos went through. He set a goal to come back in late January and play in the Olympics, and it didn't happen. It's devastating when you put a lot of pressure on yourself to do this or do that. He did the right thing. You've got to listen to your body at one point, and that's where I am right now. Listen to the trainers, strength coach and the doctors and what they say. I'll go from there."
While Robidas is preaching patience, he is still itching to get back and help the Stars push for a playoff spot. And the Stars are looking forward to his return.
"He just strengthens you," said Stars GM Jim Nill. "First of all, he's a great presence in the room. He was one of our top three defensemen before he got injured. He's a great asset to have. We're excited about him coming back. We want to be cautious, too. He's still a got a little more time to heal, but it's great to see the track he is on."


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Cavers discover Perry County is hollow
Jim McCarty
Cavers discover Perry County is hollow
Jim McCarty
Cavers discover Perry County is hollow
Jim McCarty
Jim McCarty
To the casual observer,
the Perry County corn field looks like any other located in eastern
Missouri. But in one corner of the field the land dips down to the
point that it cannot be farmed. Inside the depression is a locked iron
gate. Steam escapes past the bars into a day unwarmed by the far-off
winter sun.
One by one, a group
of people carefully slips through the gate into another world. Sudden
warmth inside — 58 degrees compared
to the single digit temperature outside — is almost a shock.
Sunlight flows into the hole and highlights limestone rock dripping
with moisture.
The occasion is a
Sunday morning outing by members of the SEMO Grotto, one of several
Missouri caving groups. Their mission is to map a section of this cave,
adding to the growing database of Missouri cave maps drawn by volunteer
They've come
to the right place. Missouri is often called "The
Cave State." Its 6,200-plus caves, a figure that grows by 100
every year as new ones are discovered, competes with Tennessee for
tops in the nation. Perry County leads the state in number of caves,
with 667, about 100 more than second place Shannon County.
Not only
does the county have the most caves, it also has the state's
longest, Crevice Cave, with 28.2 miles of mapped passages. Four
of the five longest caves in Missouri can be found in Perry County.
when a Missourian thinks of where caves are located they think
of the Ozarks," says Bob Gillespie, natural history biologist
for the Missouri Department of Conservation. "And that's
true to some extent but Perry County has by far the highest density
anywhere. It's a very karstic plain,
in that it has the limestone and dolomite that are easily erodible
and it has the sinkholes that let water get into that system."
a basement of limestone and much water trying to find its way
into the Mississippi River, the county is a veritable cave
"Perry County
is hollow," says Paul Hauck, a caving
legend who has explored Perry County caves for nearly 40 years. He
and Kris Hartman, president of the SEMO Grotto, point these facts
out to newcomers taking part in this trip, including several Illinois
residents who are members of the Little Egypt Grotto.
Inside the cave,
helmet lights flash on and soon features of the cave stand out in
stark contrast to the shadows. The group starts forward and quickly
learns that Perry County caves can be challenging, and why hard hats
are required.Just as the light from the opening disappears around a
bend, the cavers are on their knees crawling through gooey clay. The
passageway disappears into a narrow chasm, requiring a descent of faith
into the darkness.
For several hours
the trip goes on, past delicate formations of soda straws, massive
clumps of cave "bacon" and
glistening flowstone. Sometimes the cavers crawl through water. Occasionally
they can stand upright, but not for long.
Finally a large opening
appears and the cavers take a short break before Kris breaks out
a compass and tape measure and the real work begins. Rusty Lema, Rob "Bobcat" Kavaliaskas
and Kris take turns measuring, taking compass readings and
writing notes on waterproof paper. Their goal is to map a side passage
most people would never consider venturing into.
It's a tight
squeeze, but they don't hesitate. This one is comparatively
easy. Other passageways the cavers have mapped required
wet suits. It's
grueling work and not for the claustrophobic, nor the faint
of heart.
what motivates me, because it's
physically demanding," Kris
says. "It's not sitting on my butt working
on the computer. I've
always been fascinated with caves, and with exploration.
This satisfies all that."
Meanwhile, Paul leads
the rest of the cavers on a tour of the cave's
features. They slide headfirst through a slimy passageway
past a formation that looks like a wedding cake. He
knows the cave like the back of his hand, and quickly
finds a side passage that resembles a creek with broken
ice along its walls.
Walking through knee-deep
water, he shows where minerals have colored the walls orange
and black. The next section is the toughest. With
the ceiling 30 to 40 feet high, the passage between the
walls is almost too tight to get through. Yet the
reward of squeezing past is a 15-foot-high waterfall cascading
down from yet another passageway.
Paul, who lives
in Jeffriesburg, caught the caving bug in 1968 while attending Southeast
Missouri State University. By his second semester in college, he
was president of the SEMO Grotto. "I went in every Saturday and
did surveying," he
He's been known
to camp out in caves, a necessity when surveying a really long one.
wake up in total darkness," Paul says of
the experience. "You
can listen to the stream gurgle and the little
people talk. That's what
we call them. It sounds like people talking."
and the small army of other cavers search for,
photograph, map, explore, study and conserve
caves for the Missouri Speleological Survey
and other cave organizations. "Probably 80 percent of our caves are on private
land, and the MSS protects landowners' privacy by safeguarding the information
well," says
Bill Elliot, a cave biologist with the Department
of Conservation who also adds to the growing database.
"Exact cave
locations are not published, but they do track scientific information
so that qualified cavers, researchers and conservationists can contribute
to the body of knowledge."
Much work remains
to be done. Less than half of the state's caves have
been mapped. And since more are being discovered
almost daily, the work never ends. "I've got eight or
10 that we need to map that were just found," Kris
says. "That's going to take
One source of this
discovery is the "ridge walking" that
Kris does. "When
the weather is below zero, steam will
come out of a hole, just about any hole.
You stick your Maglite into it, and look
for a passage. If you have air flow,
got one definitely."
In the winter
Kris does a lot of searching, adding
potential sites to a database he keeps
on his computer. In the summer he will schedule
trips to check on his findings. "The MSS catalogs caves. But SEMO Grotto
will catalog every little hole that looks like it could be dug out later."
has experienced the thrill of being the first person to enter a cave. "That's
awesome, when you go in and everything
is pristine, no footprints."
A good hint that
a passageway hasn't
been explored is finding a 5- or 6-inch mud opening that looks like it
has passageways behind it. "Any caver would
have dug that out to make it passable," Kris
says. "So that would
tell you there hasn't been
anyone there."
While Kris
and other Missouri cavers aren't
shy about sticking their heads
into a water filled hole hoping
to find a passageway beyond,
they acknowledge that cave exploration
can be dangerous. "We have
been trained by people who know
what to do. Someone who just
gets some buddies and goes in,
that is very dangerous. That's
the whole point right there.
You shouldn't
be going in caves without being
part of an organized cave group.
We look out for each other and
follow the safety rules."
adds that state law protects
landowners from liability when
they allow cave exploration.
They also take care
of the cave and its inhabitants. "They
are very careful with the formations in the cave," MDC's Bob
Gillespie says of the grotto members. "There are certain ways you conduct
yourself in the cave. You have to know not to touch certain formations with
your bare hands. You have to know where to put your feet and how to knuckle
He says caves are
important barometers of water quality.
Part of his job is to document
what species occupy caves in
Perry County, and members of
the SEMO Grotto help with these
surveys too.
"The organisms
that use caves require pretty good water quality. And that's
important to people too.
Because the surface water that enters cave systems eventually comes
into contact with ground water. Making sure our caves are healthy,
we are ensuring people are healthy also."
Perry County's
many caves are perfect laboratories for biologists. There are
organisms found here that can't be found anywhere else on earth.
One example is the grotto
sculpin. There are also many
endangered species, though bats are less common
than in Ozark caves.
"I'm in awe all the time," Kris says
of the caves he's
been through. "Even
if I've been
somewhere 10 or 15
times, I notice something
You can contact Kris Hartman at (573) 513-0243 or at the SEMO Grotto
Web site, www.semogrotto.org. Anyone interested in cave exploring is
encouraged to join one of the many grottos located in the state. More
Missouri cave information can be found at


text:
motel, public lodging establishment for automobile travelers. Motels have traditionally differed from hotels in that the former have facilities for free parking on the premises, are seldom more than three stories high, and offer occupants direct access to rooms without having to pass through a lobby. Motels are also generally smaller and farther away from urban areas, and they offer fewer services than hotels. The distinction between motels and hotels, however, is very difficult to make, especially in the case of the so-called motor hotels, which combine the characteristics of both types of establishment. In the 1980s and 90s, some midrange motels began to offer suite accommodations and other features once found only in hotels. Motels can be seen as logical heirs to the earlier American public houses. Just as the inn was suited to 18th-century horse travel, and the hotel was suited to 19th-century railroad travel, the modern motel is suited to mass automobile travel on 20th-century expressways.
The Columbia Electronic Encyclopedia, 6th ed. Copyright © 2012, Columbia University Press. All rights reserved.
See more Encyclopedia articles on: Businesses and Occupations


text:
The Source
Comings and Goings Update: Photos capture love of Lewis & Clark
July 16, 2012
On Palatine Hill, he's known as Morgan Grether, web guru. Around Portland, he's the guitarist and singer Stone Grether. To 150,000 fans on Instagram, he's @grether, iPhone photographer extraordinaire.
Last month, Grether was named director of new media. The Source caught up with him to learn more about why he loves working at Lewis & Clark.
How did you become interested in the field of new media?
I have always been into computers, technology, gadgets. With the dominance of the web in modern life at the turn of the last century, I decided I could not sit on the sidelines any longer. I had to dive in. I am a dive-right-in-the-deep-end kind of guy, and I have been developing websites ever since. I love to be on the leading edge of what's new, what's shaping our futures. But more generally speaking, I love helping others, love helping the L&C community get the web tools we need.
What will success look like for Lewis & Clark's new media team this year, and what is your long-term vision?
This year I have several big, fun projects and a host of little ones. The most exciting one to me is what I call the "100 percent uptime" project, which means that our website should never go down. Catastrophe or minor hiccup, our website should always be up and running for anyone who needs it. With that, I want to build a strong environment of trust. I want L&C community members to always feel confident they can get the support and leadership they need from our new media team.
Longer term, we need to be able to roll with the changes in our modern lives. One way to address that is what I call the template project. We are rebuilding the shells that hold the content on all our webpages to be more easily changed around or switched out. So for instance, as new types of devices (phones, tablets, things we haven't even dreamt of yet) appear, we can push our content into different, more appropriate formats. It will help us move smoothly over the next few years of the web's surprises.
Finally, success to me as director of new media will be that I can help L&C continue progressing as a spectacular place to get an education. I want to help strengthen our community through partnerships with groups like the libraries, Information Technology, and others, and through continuing to introduce the best and most helpful tools to keep our website great. And I want to get us all (faculty, staff, students, alumni) to come together with a sense of pride and ownership of our website. It represents us to billions of people across the whole world. How cool is that?
How do you keep yourself up to date with technology?
I'm a big reader, consuming tons of tech blogs and news sites and listservs. Additionally, I go to events around town, and conferences to learn more. It takes a lot of energy to keep up, but I love it.
What part of your job excites you?
I love the constant changes of the web, the shifting sands. It's never boring. And as a lifelong learner, I love to be challenged on a daily basis.
Also, I love being where the buck stops for the L&C website, to paraphrase Harry Truman. It's a great honor, being given that responsibility for a place I love so much.
What do you like to do in your spare time?
I'll say three things. First off, I love being a dad to my amazing family. That's always top priority for my time and endlessly enjoyable. Secondly, I'm a singer-songwriter, playing around town in different little nooks and crannies. And thirdly, photography has become a great passion of mine the past couple of years. In particular, I have gotten into Instagram, an incredibly fun social media app for taking and discussing pictures. I have nearly 150,000 followers there. I helped pioneer the notion of Instagram meet-ups, and we have been holding monthly get-togethers here in Portland for over a year and half. It's a wonderful way to meet new people from all across the area.
What can you share about yourself that might surprise some people?
I was a Kansas farm boy, living out in the middle of nowhere, until third grade. Technology for me as a kid was a tractor. But since then I've traveled the world, spending summers in Paris, the Riviera, Madrid, and more. And now I'd be lost without my laptop and smart phone!
Additionally, I have a PhD in English and have taught literature off and on for years. My expertise is America and Britain in the 19th and 20th centuries. Let's talk poetry!
Comings and Goings Update
Several people have joined the community recently, and some continuing employees have taken on new roles and responsibilities at Lewis & Clark:
Mandy Alperin, development assistant, Institutional Advancement; Mark Dahl, director of Aubrey R. Watzek Library; Jared Delahaye, lab technician, Department of Biology; Morgan Grether, director of new media, Public Affairs and Communications; Lindsay Kadish, program coordinator, Business Law Programs; Barbara Lipinski, compensation and benefits analyst, Human Resources; Sarah Petersen, director of alumni relations, Law Alumni Relations; and Tracy Sullivan, director of career services, Law Career and Professional Development Center.
The following people have left Lewis & Clark. Here's wishing them good luck in their new adventures:
Kylee Brandt, admissions counselor, CAS Admissions; Marsha Dexter, accountant, College Bookstore; Chelsea Harper, program coordinator, Center for Community Engagement; Susan Hubbuch, director, Writing Center; Robin Jerke, director of alumni relations, Law School Alumni Relations; Ellen Jones, director, Law Career Services; Stacie Pacheco, program assistant, Business Law Program; Corey Parrish, campus safety officer, Campus Safety; Nicole Pelletier, lab assistant, Department of Biology; and John Stewart, area director, Campus Living.


text:
Free delivery over £50
Free 100-day returns and express refunds
We price match, and carbon offset deliveries
"Gant began as a shirtmaker in 1949 and has been evolving ever since. It introduced colourful Oxford shirts to its collection in the 50s, becoming a favourite with Ivy Leaguers, but you don't need a Harvard degree to pull off these timeless pieces."
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text:
Bayfield Training – Introduction to Shopping Centre Investments
Date(s) - 20/05/2019 - 22/05/2019
9:00 am - 6:00 pm
Holiday Inn - Stratford City
Learn how to engage shopping centre owner, leasing agent and manager throughout the value chain and maximise centre profits.
Discover new perspectives on shopping centre economics, organisational structure, innovative income generation, the latest techniques to analyse performance and finally well researched opinion on the future many paths within the sector.
The course provides everything you need to succesfully ride the wave of new technology and rapid social change. On completion you will have the tools to help you make the most of your investment as well as compete globally at both the asset and at the portfolio level.
"Why are Shopping Centres unique?"
- Introduction to Shopping Centre Investment (the Profit Cycle and Value Chain)
- Shopping Centre Need & Location Analysis (GIS and Data)
- Design, Construction, Repairs & Refurbishment (Development Appraisals)
"How do you run a succesful Shopping Centre?"
- Operational Management, Marketing and Expenditure (Running Cost Analysis)
- Occupiers, Leases and Optimisation Modelling (Product Mix, full cash flow models and impacts of lease covenants)
"How do you enhance Shopping Centre performance?"
- Performance Metrics, Reducing Spend and Increasing Efficiency (Footfall Intelligence and Impact on Investment)
- Commercialisation and New Technology (Turnover enhancement and customer experience)
- Shopping Centre Portfolios (Industry benchmarking)
- Sustainability across the Shopping Centre lifecyle (new performance metrics and opportunities for profit)
If you or your employees need to get up to date fast on this unique and exciting sector enrol today on Shopping Centre Investment.
The course also includes a networking dinner on the first evening.
For more information visit – Bayfield Training


text:
5 members0 Comments 0 Likes
Posted on August 23, 2012 at 6:00am 0 Comments 0 Likes
The dance solo called Paces is part of the Antibodies Cycles, in which Petra Zanki and Britta
Wirthmüller deal with the bodies that "fall through the matrix of what is normally accepted or
valued as possible." The project focuses on those marginal bodies that are, like some sort
of a Minotaur,…Continue
Posted on August 19, 2012 at 3:57am 0 Comments 1 Like
For the start, it is performed by three dancers (Antonija Livingstone, Alex Baczynski-Jenkins and An Kaler herself) whose skills as dancers are outstanding. By skills, I don't mean…Continue
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