Neuroregeneration

Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.
Nervous system injuries affect over 90,000 people every year. It is estimated that spinal cord injuries alone affect 10,000 each year. As a result of this high incidence of neurological injuries, nerve regeneration and repair, a subfield of neural tissue engineering, is becoming a rapidly growing field dedicated to the discovery of new ways to recover nerve functionality after injury. The nervous system is divided into two parts: the central nervous system, which consists of the brain and spinal cord, and the peripheral nervous system, which consists of cranial and spinal nerves along with their associated ganglia. While the peripheral nervous system has an intrinsic ability for repair and regeneration, the central nervous system is, for the most part, incapable of self-repair and regeneration. There is currently no treatment for recovering human nerve function after injury to the central nervous system. In addition, multiple attempts at nerve re-growth across the PNS-CNS transition have not been successful. There is simply not enough knowledge about regeneration in the central nervous system. In addition, although the peripheral nervous system has the capability for regeneration, much research still needs to be done to optimize the environment for maximum regrowth potential. Neuroregeneration is important clinically, as it is part of the pathogenesis of many diseases, including multiple sclerosis.
Peripheral nervous system regeneration.
Neuroregeneration in the peripheral nervous system (PNS) occurs to a significant degree. After an injury to the axon, peripheral neurons activate a variety of signaling pathways which turn on pro-growth genes, leading to reformation of a functional growth cone and regeneration. The growth of these axons is also governed by chemotactic factors secreted from Schwann cells. Injury to the peripheral nervous system immediately elicits the migration of phagocytes, Schwann cells, and macrophages to the lesion site in order to clear away debris such as damaged tissue which is inhibitory to regeneration. When a nerve axon is severed, the end still attached to the cell body is labeled the proximal segment, while the other end is called the distal segment. After injury, the proximal end swells and experiences some retrograde degeneration, but once the debris is cleared, it begins to sprout axons and the presence of growth cones can be detected. The proximal axons are able to regrow as long as the cell body is intact, and they have made contact with the Schwann cells in the endoneurium (also known as the endoneurial tube or channel). Human axon growth rates can reach 2 mm/day in small nerves and 5 mm/day in large nerves. The distal segment, however, experiences Wallerian degeneration within hours of the injury; the axons and myelin degenerate, but the endoneurium remains. In the later stages of regeneration the remaining endoneurial tube directs axon growth back to the correct targets. During Wallerian degeneration, Schwann cells grow in ordered columns along the endoneurial tube, creating a band of Büngner cells that protects and preserves the endoneurial channel. Also, macrophages and Schwann cells release neurotrophic factors that enhance re-growth.
Central nervous system regeneration.
Unlike peripheral nervous system injury, injury to the central nervous system is not followed by extensive regeneration. It is limited by the inhibitory influences of the glial and extracellular environment. The hostile, non-permissive growth environment is, in part, created by the migration of myelin-associated inhibitors, astrocytes, oligodendrocytes, oligodendrocyte precursors, and microglia. The environment within the CNS, especially following trauma, counteracts the repair of myelin and neurons. Growth factors are not expressed or re-expressed; for instance, the extracellular matrix is lacking laminins. Glial scars rapidly form, and the glia actually produce factors that inhibit remyelination and axon repair; for instance, NOGO and NI-35. The axons themselves also lose the potential for growth with age, due to a decrease in GAP43 expression, among others.
Slower degeneration of the distal segment than that which occurs in the peripheral nervous system also contributes to the inhibitory environment because inhibitory myelin and axonal debris are not cleared away as quickly. All these factors contribute to the formation of what is known as a glial scar, which axons cannot grow across. The proximal segment attempts to regenerate after injury, but its growth is hindered by the environment. It is important to note that central nervous system axons have been proven to regrow in permissive environments; therefore, the primary problem to central nervous system axonal regeneration is crossing or eliminating the inhibitory lesion site. Another problem is that the morphology and functional properties of central nervous system neurons are highly complex, for this reason a neuron functionally identical cannot be replaced by one of another type (Llinás' law).
Inhibition of axonal regrowth.
Glial cell scar formation is induced following damage to the nervous system. In the central nervous system, this glial scar formation significantly inhibits nerve regeneration, which leads to a loss of function. Several families of molecules are released that promote and drive glial scar formation. For instance, transforming growth factors B-1 and -2, interleukins, and cytokines play a role in the initiation of scar formation. The accumulation of reactive astrocytes at the site of injury and the up regulation of molecules that are inhibitory for neurite outgrowth contribute to the failure of neuroregeneration. The up-regulated molecules alter the composition of the extracellular matrix in a way that has been shown to inhibit neurite outgrowth extension. This scar formation involves several cell types and families of molecules.
Chondroitin sulfate proteoglycan.
In response to scar-inducing factors, astrocytes up regulate the production of chondroitin sulfate proteoglycans. Astrocytes are a predominant type of glial cell in the central nervous system that provide many functions including damage mitigation, repair, and glial scar formation. The RhoA pathway is involved. Chondroitin sulfate proteoglycans (CSPGs) have been shown to be up regulated in the central nervous system (CNS) following injury. Repeating disaccharides of glucuronic acid and galactosamine, glycosaminoglycans (CS-GAGs), are covalently coupled to the protein core CSPGs. CSPGs have been shown to inhibit regeneration in vitro and in vivo, but the role that the CSPG core protein vs. CS-GAGs had not been studied until recently.
Keratan sulfate proteoglycans.
Like the chondroitin sulfate proteoglycans, keratan sulfate proteoglycan (KSPG) production is up regulated in reactive astrocytes as part of glial scar formation. KSPGs have also been shown to inhibit neurite outgrowth extension, limiting nerve regeneration. Keratan sulfate, also called keratosulfate, is formed from repeating disaccharide galactose units and N-acetylglucosamines. It is also 6-sulfated. This sulfation is crucial to the elongation of the keratan sulfate chain. A study was done using N-acetylglucosamine 6-O-sulfotransferase-1 deficient mice. The wild type mouse showed a significant up regulation of mRNA expressing N-acetylglucosamine 6-O-sulfotransferase-1 at the site of cortical injury. However, in the N-acetylglucosamine 6-O-sulfotransferase-1 deficient mice, the expression of keratan sulfate was significantly decreased when compared to the wild type mice. Similarly, glial scar formation was significantly reduced in the N-acetylglucosamine 6-O-sulfotransferase-1 mice, and as a result, nerve regeneration was less inhibited.
Other inhibitory factors.
Proteins of oligodendritic or glial debris origin that influence neuroregeneration:
Clinical treatments.
Surgery.
Surgery can be done in case a peripheral nerve has become cut or otherwise divided. This is called peripheral nerve reconstruction. The injured nerve is identified and exposed so that normal nerve tissue can be examined above and below the level of injury, usually with magnification, using either loupes or an operating microscope. If a large segment of nerve is harmed, as can happen in a crush or stretch injury, the nerve will need to be exposed over a larger area. Injured portions of the nerve are removed. The cut nerve endings are then carefully reapproximated using very small sutures. The nerve repair must be covered by healthy tissue, which can be as simple as closing the skin or it can require moving skin or muscle to provide healthy padded coverage over the nerve. The type of anesthesia used depends on the complexity of the injury. A surgical tourniquet is almost always used.
Prognosis.
The expectations after surgical repair of a divided peripheral nerve depends on several factors:
Autologous nerve grafting.
Currently, autologous nerve grafting, or a nerve autograft, is known as the gold standard for clinical treatments used to repair large lesion gaps in the peripheral nervous system. It is important that nerves are not repaired under tension, which could otherwise happen if cut ends are reapproximated across a gap. Nerve segments are taken from another part of the body (the donor site) and inserted into the lesion to provide endoneurial tubes for axonal regeneration across the gap. However, this is not a perfect treatment; often the final outcome is only limited function recovery. Also, partial de-innervation is frequently experienced at the donor site, and multiple surgeries are required to harvest the tissue and implant it.
When appropriate, a nearby donor may be used to supply innervation to lesioned nerves. Trauma to the donor can be minimized by utilizing a technique known as end-to-side repair. In this procedure, an epineurial window is created in the donor nerve and the proximal stump of the lesioned nerve is sutured over the window. Regenerating axons are redirected into the stump. Efficacy of this technique is partially dependent upon the degree of partial neurectomy performed on the donor, with increasing degrees of neurectomy giving rise to increasing axon regeneration within the lesioned nerve, but with the consequence of increasing deficit to the donor.
Some evidence suggests that local delivery of soluble neurotrophic factors at the site of autologous nerve grafting may enhance axon regeneration within the graft and help expedite functional recovery of a paralyzed target. Other evidence suggests that gene-therapy induced expression of neurotrophic factors within the target muscle itself can also help enhance axon regeneration. Accelerating neuroregeneration and the reinnervation of a denervated target is critically important in order to reduce the possibility of permanent paralysis due to muscular atrophy.
Allografts and xenografts.
Variations on the nerve autograft include the allograft and the xenograft. In allografts, the tissue for the graft is taken from another person, the donor, and implanted in the recipient. Xenografts involve taking donor tissue from another species. Allografts and xenografts have the same disadvantages as autografts, but in addition, tissue rejection from immune responses must also be taken into account. Often immunosuppression is required with these grafts. Disease transmission also becomes a factor when introducing tissue from another person or animal. Overall, allografts and xenografts do not match the quality of outcomes seen with autografts, but they are necessary when there is a lack of autologous nerve tissue.
Nerve guidance conduit.
Because of the limited functionality received from autografts, the current gold standard for nerve regeneration and repair, recent neural tissue engineering research has focused on the development of bioartificial nerve guidance conduits in order to guide axonal regrowth. The creation of artificial nerve conduits is also known as entubulation because the nerve ends and intervening gap are enclosed within a tube composed of biological or synthetic materials.
Immunisation.
A direction of research is towards the use of drugs that target remyelinating inhibitor proteins, or other inhibitors. Possible strategies include vaccination against these proteins (active immunisation), or treatment with previously created antibodies (passive immunisation). These strategies appear promising on animal models with experimental autoimmune encephalomyelitis (EAE), a model of MS.
Monoclonal antibodies have also been used against inhibitory factors such as NI-35 and NOGO.


Cortico-basal ganglia-thalamo-cortical loop

The cortico-basal ganglia-thalamo-cortical loop (CBGTC loop) is a system of neural circuits in the brain. The loop involves connections between the cortex, the basal ganglia, the thalamus, and back to the cortex. It is of particular relevance to hyperkinetic and hypokinetic movement disorders, such as Parkinson's disease and Huntington's disease, as well as to mental disorders of control, such as attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and Tourette syndrome.
The CBGTC loop primarily consists of modulatory dopaminergic projections from the pars compacta of the substantia nigra, and ventral tegmental area as well as excitatory glutamatergic projections from the cortex to the striatum, where these projections form synapses with excitatory and inhibitory pathways that relay back to the cortex. The loop was originally proposed as a part of a model of the basal ganglia called the "parallel processing model", which has been criticized and modified into another model called the "center surround model".
Current organization schemes characterize cortico-basal ganglia interactions as segregated parallel processing, meaning there is little convergence of distinct cortical areas in the basal ganglia. This is thought to explain the topographically organized functionality of the striatum. The striatum is organized on a rostro-caudal axis, with the rostral putamen and caudate serving associative and cognitive functions and the caudal areas serving sensorimotor function. Sometimes when the striatum is the expressed target the loop is referred to as the cortico-striatal-thalamic-cortical loop.
Neuroanatomy.
The two major input structures of the circuit are the striatum and the subthalamic nucleus (STN). The striatum receives inputs from both the cortex and the pars compacta of the substantia nigra (SNc), while the STN only receives cortical inputs.
Two pathways emerge from the striatum. One pathway is called the indirect (or NoGo) pathway and is inhibitory. This projects to and inhibits the globus pallidus externus (GPe), resulting in the disinhibition of the globus pallidus internus (GPi), leading to inhibition of the thalamus. This pathway also, as a result of inhibiting the GPe, disinhibits the subthalamic nucleus, which results in excitation of the GPi, and therefore inhibition of the thalamus.
The second pathway, is called the direct (or Go) pathway and is excitatory. This pathway inhibits the GPi, resulting in the disinhibition of the thalamus. The direct pathway mostly consists of monosynaptic connections driven by dopamine receptor D1, adenosine A1 receptor, and muscarinic acetylcholine receptor M4, while the indirect pathway relies on connections driven by dopamine receptor D2, adenosine A2A receptor, and muscarinic acetylcholine receptor M1.
The parallel CBGTC loops have been segregated according to the functions of associated cortical regions. One scheme involves the division into limbic and motor loops, with the motor loops containing indirect and direct pathways, which are in turn interconnected with the limbic loop that projects into the ventral striatum. The loop has also been divided into limbic, associative, oculomotor, and motor circuits to explain the role of dopamine in the basal ganglia on motivational states. A five loop division based on primary cortical targets has been described as follows:
A problem identified with the current anatomy of the circuit is that the time delay between the direct and indirect pathways should result in this circuit not working. To overcome this, the center surround hypothesis posits a hyperdirect pathway from the cortex would inhibit other inputs besides one focused cortical input. However, the timing of basal ganglia activity and limb moment, as well as lesion studies do not support this hypothesis
Function.
Two models have been proposed to explain how actions are selected in the basal ganglia. The actor-critic model suggests that actions are generated and evaluated by a "critic" in the ventral striatum, while the actions are carried out by an "actor" in the dorsal striatum. Another model proposes the basal ganglia acts as a selection mechanism, where actions are generated in the cortex and are selected based on context by the basal ganglia. The CBGTC loop is also involved in reward discounting, with firing increasing with an unexpected or greater than expected reward. One review supported the idea that the cortex was involved in learning actions regardless of their outcome, while the basal ganglia was involved in selecting appropriate actions based on associative reward based trial and error learning.
Role in disease.
The CBGTC loop has been implicated in many diseases. For example, in Parkinson's disease, degeneration of dopaminergic neurons leading to decreased activity of the excitatory pathway is thought to result in hypokinesia, and in Huntington's disease, degeneration of GABAergic neurons driving the inhibitory pathway is thought to result in the jerky body movements. The co-degeneration of limbic projections along with motor projections may result in many of the psychiatric symptoms of these primarily motor illnesses. In OCD, the loop may be dysfunctional, with an imbalance between the indirect and direct pathways resulting in unwanted thoughts, getting "stuck". In ADHD, decreased tonic dopaminergic signaling resulting in excessive discounting of delayed rewards is thought to result in decreased attention.
Research.
The CBGTC loop has been studied in relation to consciousness, action selection, in relation to other circuits and in the context of memory and cognition. The CBGTC loop model has been criticized as oversimplified and too rigidly applied, given evidence of anatomical and functional overlap and interactions between the direct and indirect pathways. The loop has also been researched in the context of deep brain stimulation. As of 2013 there was intense debate with regards to division of the circuit, pathway interactions, number of pathways and general anatomy.


Axonal transport

Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytoplasm of its axon called the axoplasm. Since some axons are on the order of meters long, neurons cannot rely on diffusion to carry products of the nucleus and organelles to the end of their axons. Axonal transport is also responsible for moving molecules destined for degradation from the axon back to the cell body, where they are broken down by lysosomes.
Movement toward the cell body is called retrograde transport and movement toward the synapse is called anterograde transport.
Mechanism.
The vast majority of axonal proteins are synthesized in the neuronal cell body and transported along axons. Some mRNA translation has been demonstrated within axons. Axonal transport occurs throughout the life of a neuron and is essential to its growth and survival. Microtubules (made of tubulin) run along the length of the axon and provide the main cytoskeletal "tracks" for transportation. Kinesin and dynein are motor proteins that move cargoes in the anterograde (forwards from the soma to the axon tip) and retrograde (backwards to the soma (cell body)) directions, respectively. Motor proteins bind and transport several different cargoes including mitochondria, cytoskeletal polymers, autophagosomes, and synaptic vesicles containing neurotransmitters.
Axonal transport can be fast or slow, and anterograde (away from the cell body) or retrograde (conveys materials from axon to cell body).
Fast and slow transport.
Vesicular cargoes move relatively fast (50–400 mm/day) whereas transport of soluble (cytosolic) and cytoskeletal proteins takes much longer (moving at less than 8 mm/day). The basic mechanism of fast axonal transport has been understood for decades but the mechanism of slow axonal transport is only recently becoming clear, as a result of advanced imaging techniques. Fluorescent labeling techniques (e.g. fluorescence microscopy) have enabled direct visualization of transport in living neurons. (See also: Anterograde tracing.)
Recent studies have revealed that the movement of cytoskeletal "slow" cargoes is actually rapid but unlike fast cargoes, they pause frequently, making the overall transit rate much slower. The mechanism is known as the "Stop and Go" model of slow axonal transport, and has been extensively validated for the transport of the cytoskeletal protein neurofilament. The movement of soluble (cytosolic) cargoes is more complex, but appears to have a similar basis where soluble proteins organize into multi-protein complexes that are then conveyed by transient interactions with more rapidly moving cargoes moving in fast axonal transport. An analogy is the difference in transport rates between local and express subway trains. Though both types of train travel at similar velocities between stations, the local train takes much longer to reach the end of the line because it stops at every station whereas the express makes only a few stops on the way.
Anterograde transport.
Anterograde (also called "orthograde") transport is movement of molecules/organelles outward, from the cell body (also called soma) to the synapse or cell membrane.
The anterograde movement of individual cargoes (in transport vesicles) of both fast and slow components along the microtubule is mediated by kinesins. Several kinesins have been implicated in slow transport, though the mechanism for generating the "pauses" in the transit of slow component cargoes is still unknown.
There are two classes of slow anterograde transport: slow component a (SCa) that carries mainly microtubules and neurofilaments at 0.1-1 millimeters per day, and slow component b (SCb) that carries over 200 diverse proteins and actin at a rate of up to 6 millimeters per day. The slow component b, which also carries actin, are transported at a rate of 2-3 millimeters per day in retinal cell axons.
During reactivation from latency, the herpes simplex virus (HSV) enters its lytic cycle, and uses anterograde transport mechanisms to migrate from dorsal root ganglia neurons to the skin or mucosa that it subsequently affects.
A cargo-receptor for anterograde transport motors, the kinesins, has been identified as the amyloid precursor protein (APP), the parent protein that produces the senile plaques found in Alzheimer's disease. A 15-amino acid peptide in the cytoplasmic carboxyl terminus of APP binds with high affinity to conventional kinesin-1 and mediates transport of exogenous cargo in the giant axon of the squid.
Manganese, a contrast agent for T1-weighted MRI, travels by anterograde transport after stereotaxic injection into the brain of experimental animals and thereby reveals circuitry by whole brain MR imaging in living animals, as pioneered by Robia Pautler, Elaine Bearer and Russ Jacobs. Studies in kinesin-light chain-1 knocked out mice revealed that Mn2+ travels by kinesin-based transport in the optic nerve and in the brain. Transport in both hippocampal projections and in the optic nerve also depends on APP. Transport from hippocampus to forebrain is decreased in aging and destination is altered by the presence of Alzheimer's disease plaques.
Retrograde transport.
Retrograde transport shuttles molecules/organelles away from axon termini toward the cell body. Retrograde axonal transport is mediated by cytoplasmic dynein, and is used for example to send chemical messages and endocytosis products headed to endolysosomes from the axon back to the cell. Operating at average "in vivo" speeds of approximately 2 μm/sec, fast retrograde transport can cover 10-20 centimeters per day.
Fast retrograde transport returns used synaptic vesicles and other materials to the soma and informs the soma of conditions at the axon terminals. Retrograde transport carries survival signals from the synapse back to the cell body, such as the TRK, the nerve growth factor receptor. Some pathogens exploit this process to invade the nervous system. They enter the distal tips on an axon and travel to the soma by retrograde transport. Examples include tetanus toxin and the herpes simplex, rabies, and polio viruses. In such infections, the delay between infection and the onset of symptoms corresponds to the time needed for the pathogens to reach the somata. Herpes simplex virus travels both ways in axons depending on its life cycle, with retrograde transport dominating polarity for incoming capsids.
Consequences of interruption.
Whenever axonal transport is inhibited or interrupted, normal physiology becomes pathophysiology, and an accumulation of axoplasm, called an axonal spheroid, may result. Because axonal transport can be disrupted in a multitude of ways, axonal spheroids can be seen in many different classes of diseases, including genetic, traumatic, ischemic, infectious, toxic, degenerative and specific white matter diseases called leukoencephalopathies. Several rare neurodegenerative diseases are linked to genetic mutations in the motor proteins, kinesin and dynein, and in those cases it is likely that axonal transport is a key player in mediating pathology. Dysfunctional axonal transport is also linked to sporadic (common) forms of neurodegenerative diseases such as Alzheimer's and Parkinson's. This is mainly due to numerous observations that large axonal accumulations are invariably seen in affected neurons, and that genes known to play a role in the familial forms of these diseases also have purported roles in normal axonal transport. However, there is little direct evidence for involvement of axonal transport in the latter diseases, and other mechanisms (such as direct synaptotoxicity) may be more relevant.
Arrest of axoplasmic flow at the edge of ischemic area in vascular retinopathies lead to swelling of nerve fibres which give rise to soft exudates or cotton-wool patches.
Since the axon depends on axoplasmic transport for vital proteins and materials, injury such as diffuse axonal injury that interrupts the transport will cause the distal axon to degenerate in a process called Wallerian degeneration. Cancer drugs that interfere with cancerous growth by altering microtubules (which are necessary for cell division) damage nerves because the microtubules are necessary for axonal transport.
Infection.
The rabies virus reaches the central nervous system by retrograde axoplasmic flow. The tetanus neurotoxin is internalised at the neuromuscular junction through binding the nidogen proteins and is retrogradely transported towards the soma in signaling endosomes. Neurotropic viruses, such the herpesviruses, travel inside axons using cellular transport machinery, as has been shown in work by Elaine Bearer's group. Other infectious agents are also suspected of using axonal transport. Such infections are now thought to contribute to Alzheimer's disease and other neurodegenerative neurological disorders.


Sister college

In some countries, certain universities have a tradition of pairing their residential colleges or houses with one another. Colleges that are paired are referred to as sister colleges, and have a ceremonial and symbolic relationship to one another. Some notable pairs include Harvard University and Yale University, the University of Oxford and the University of Cambridge, and the University of York and Durham University. Students at one college can often find accommodation at their sister college should they be visiting the other University; this is especially relevant to Harvard and Yale students during the annual Game.
Ireland.
Secondary schools in Ireland which are run by the same religious order are often referred to as "sister colleges" and enjoy a privileged relationship with one another. For example, the Jesuit Belvedere College and Clongowes Wood College are sister colleges, as are the Spiritan Blackrock College and St. Michael's College, Dublin.


Loop-invariant code motion

In computer programming, loop-invariant code consists of statements or expressions (in an imperative programming language) which can be moved outside the body of a loop without affecting the semantics of the program. Loop-invariant code motion (also called hoisting or scalar promotion) is a compiler optimization which performs this movement automatically.
Example.
In the following code sample, two optimizations can be applied.
int i = 0;
while (i < n) {
 x = y + z;
 a[i] = 6 * i + x * x;
 ++i;
Although the calculation codice_1 and codice_2 is loop-invariant, precautions must be taken before moving the code outside the loop. It is possible that the loop condition is codice_3 (for example, if codice_4 holds a negative value), and in such case, the loop body should not be executed at all. One way of guaranteeing correct behaviour is using a conditional branch outside of the loop. Evaluating the loop condition can have side effects, so an additional evaluation by the codice_5 construct should be compensated by replacing the codice_6 loop with a codice_7. If the code used codice_7 in the first place, the whole guarding process is not needed, as the loop body is guaranteed to execute at least once.
int i = 0;
if (i < n) {
 x = y + z;
 int const t1 = x * x;
 do {
 a[i] = 6 * i + t1;
 ++i;
 } while (i < n);
This code can be optimized further. For example, strength reduction could remove the two multiplications inside the loop (codice_9 and codice_10), and induction variable elimination could then elide codice_11 completely. Since codice_12 must be in lock step with codice_11 itself, there is no need to have both.
Invariant code detection.
Usually, a reaching definitions analysis is used to detect whether a statement or expression is loop invariant.
For example, if all reaching definitions for the operands of some simple expression are outside of the loop, the expression can be moved out of the loop.
Recent work using data-flow dependence analysis allows to detect not only invariant commands but larger code fragments such as an inner loop. The analysis also detects quasi-invariants of arbitrary degrees, that is commands or code fragments that become invariant after a fixed number of iterations of the loop body.
Benefits.
Loop-invariant code which has been hoisted out of a loop is executed less often, providing a speedup. Another effect of this transformation is allowing constants to be stored in registers and not having to calculate the address and access the memory (or cache line) at each iteration.
However, if too many variables are created, there will be high register pressure, especially on processors with few registers, like the 32-bit x86. If the compiler runs out of registers, some variables will be spilled. To counteract this, the inverse optimization can be performed, rematerialization.


Soma (biology)

The soma (pl. "somas"), perikaryon (pl. "perikarya"), neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. The word 'soma' comes from the Greek "σῶμα", meaning 'body'. Although it is often used to refer to neurons, it can also refer to other cell types as well, including astrocytes, oligodendrocytes, and microglia. There are many different specialized types of neurons, and their sizes vary from as small as about 5 micrometres to over 10 millimetres for some of the smallest and largest neurons of invertebrates, respectively.
The soma of a neuron (i.e., the main part of the neuron in which the dendrites branch off of) contains many organelles, including granules called Nissl granules, which are composed largely of rough endoplasmic reticulum and free polyribosomes. The cell nucleus is a key feature of the soma. The nucleus is the source of most of the RNA that is produced in neurons. In general, most proteins are produced from mRNAs that do not travel far from the cell nucleus. This creates a challenge for supplying new proteins to axon endings that can be a meter or more away from the soma. Axons contain microtubule-associated motor proteins that transport protein-containing vesicles between the soma and the synapses at the axon terminals. Such transport of molecules towards and away from the soma maintains critical cell functions. In case of neurons, the soma receives a large number of inhibitory synapses, which can regulate the activity of these cells. It has also been shown, that microglial processes constantly monitor neuronal functions through somatic junctions, and exert neuroprotection when needed.
The axon hillock is a specialized domain of the neuronal cell body from which the axon originates. A high amount of protein synthesis occurs in this region, as it contains many Nissl granules (which are ribosomes wrapped in RER) and polyribosomes. Within the axon hillock, materials are sorted as either items that will enter the axon (like the components of the cytoskeletal architecture of the axon, mitochondria, etc.) or will remain in the soma. In addition, the axon hillock also has a specialized plasma membrane that contains large numbers of voltage-gated ion channels, since this is most often the site of action potential initiation.
The survival of some sensory neurons depends on axon terminals making contact with sources of survival factors that prevent apoptosis. The survival factors are neurotrophic factors, including molecules such as nerve growth factor (NGF). NGF interacts with receptors at axon terminals, and this produces a signal that must be transported up the length of the axon to the nucleus. A current theory of how such survival signals are sent from axon endings to the soma includes the idea that NGF receptors are endocytosed from the surface of axon tips and that such endocytotic vesicles are transported up the axon.


Vatutine

Vatutine ( ) is a city in Zvenyhorodka Raion, Cherkasy Oblast (region) of Ukraine. It hosts the administration of Vatutine urban hromada, one of the hromadas of Ukraine. Population:
History.
Founded in 1946, city since 1952.
In January 1989 the population of the city was 20362 people
In January 2013 the population of the city was 17 653 people.
Until 18 July 2020, Vatutine was designated as a city of oblast significance and belonged to Vatutine Municipality but not to any raion. As part of the administrative reform of Ukraine, which reduced the number of raions of Cherkasy Oblast to four, the city was merged into Zvenyhorodka Raion.


30-day yield

In the United States, 30-day yield is a standardized yield calculation for bond funds. The formula for calculating 30-day yield is specified by the U.S. Securities and Exchange Commission (SEC). The formula translates the bond fund's current portfolio income into a standardized yield for reporting and comparison purposes. A bond fund's 30-day yield may appear in the fund's "Statement of Additional Information (SAI)" in its prospectus.
Because the 30-day yield is a standardized mandatory calculation for all United States bond funds, it serves as a common ground comparison of yield performance. Its weakness lies in the fact that funds tend to trade actively and do not hold bonds until maturity. In addition, funds do not mature. For this reason, analysts often consider a distribution yield to be a better measure of a fund's income-generating potential.
United States money market funds report a 7-day SEC yield. The rate expresses how much the fund would yield if it paid income at the same level as it did in the prior 7 days for a whole year. It is calculated by taking the sum of the income paid out over the period divided by 7, and multiplying that quantity by 36500 (365 days x 100).
Bond fund yield calculation.
The SEC yield calculation for a bond fund is essentially an annualized version of the interest and dividends per share earned over the last month, divided by the share price. It is not the same as the yield to maturity for the bonds in the portfolio, as it does not take into account the amortization of the premiums or discounts at which the bonds are trading. Because bond funds trade actively and prices fluctuate, the rate may not be a good indicator of future results. However, because the calculation is standardized, it provides a standard comparison measure for funds. An appropriate use is to make daily/weekly adjustments to a bond mutual fund price series to determine running total return.
The formula for SEC 30-day yield is formula_1
Where:


Operations readiness and assurance

Operations readiness and assurance (OR&A) is a process used in the performance of primarily oil, gas and energy projects, to measure progress towards achieving the state of "readiness to operate".
OR&A also includes an assurance component which gives an ongoing, real-time indication of the likelihood that the project will achieve that state by the time of handover to the eventual owner/operator.
Operations Readiness.
Operations readiness is the process of preparing the custodians of an asset under construction, and their supporting organisation, to be fully ready to assume ownership of the asset at the point of delivery/handover, and to be able to take responsibility for performing the safe and efficient operation of that asset in a sustainable and environmentally-friendly manner.
Assurance.
Assurance refers to stakeholders in a project who cannot wait until a project is completed, and handover to the operations team imminent, to discover that something has been omitted or overlooked which would subsequently prevent operation of the asset in the manner stated above.
The word 'assurance' refers to the act of reassuring the various stakeholders in a project or venture that their asset and organisation is in a state of operations readiness, or providing a measure of assurance that it will be by the time it is required.
Implementing methods.
The first issue facing an OR&A practitioner on a project is how to disseminate the vast amount of information required to implement OR&A in a way that neither 'swamps' users in a sea of information nor 'starves' them of vital information required to complete the various activities and tasks at the appropriate time.
Some methods developed to address this problem involve the use of a secure private cloud-based system, to allow the user to manage the volume of information within the system, and to present it in a manageable way. This system, accessed though a secure login over the internet, provides a central point for the management of information, minimising the maintenance requirements for the system, and ensuring that all users can access the information.


Mental nerve

Mental nerve is a sensory nerve which provides sensation to the front of the chin and lower lip as well as the labial gingivae of the mandibular anterior teeth and the premolars. It is a branch of the posterior trunk of the inferior alveolar nerve, which is itself a branch of the mandibular division of the trigeminal nerve (CN V).
The nerve emerges at the mental foramen in the mandible, and divides beneath the Depressor anguli oris muscle into three branches:
These branches communicate freely with the facial nerve.
Clinical significance.
The mental nerve can be blocked with local anesthesia, a procedure used in surgery of the chin, lower lip and buccal mucosa from midline to the second premolar. In this technique, local anesthetic is infiltrated in the soft tissue surrounding the mental foramen.


International Brain Research Organization

The International Brain Research Organization (IBRO) is the global federation of neuroscience organizations that aims to promote and support neuroscience around the world through training, teaching, collaborative research, advocacy and outreach. More than 90 international, national and regional scientific organisations constitute IBRO’s Governing Council which, together with the five IBRO Regional Committees, address the needs and advance the work of individual scientists and research communities everywhere. In addition, IBRO has partnerships with like-minded scientific societies and organizations to identify priorities and help bridge gaps in knowledge, investment and resources in the field of brain research.
History.
IBRO was founded in 1961 in response to the growing demand from neuroscientists around the world for the creation of a central organization that would cut across world boundaries and improve communication and collaboration among brain researchers.
The origin of IBRO can be traced back to a meeting of electroencephalographers in London in 1947, which led to the establishment of an International Federation of EEG and Clinical Neurophysiology. A later conference in Moscow in 1958 of IFEEG and other groups, successfully achieved unanimous support for a resolution proposing the creation of an international organization representing brain research worldwide.
IBRO was established as an independent, non-governmental organization, regulated by a Governing Council. The organization represents the interests of circa 75,000 neuroscientists around the globe.
Quadriennial meeting.
In collaboration with neuroscience societies around the world, IBRO holds international congresses once every four years.
IBRO World Congresses:
Presidents.
IBRO Presidents:


Pamela Britton

Pamela Britton (born Armilda Jane Owen, March 19, 1923 – June 17, 1974) was an American actress, best known for appearing as Lorelei Brown in the television series "My Favorite Martian" (1963–1966) and for her female lead in the film noir classic "D.O.A." (1950). Throughout her acting career, Britton appeared often on Broadway and in several Hollywood and TV movies.
Early career.
Armilda Jane Owen was born in Milwaukee, Wisconsin. Owen's father, Raymond G. Owen, was a doctor who died when she was 3 years old. Her mother was Ethel Waite Owen, a prominent stage, radio, and early television actress. She had two sisters: Virginia, who was actress for RKO Radio Pictures; and Mary, a social worker.
Owen attended Holy Angels Academy and the State Teacher's Normal School in her home town of Milwaukee. By the age of nine she was doing summer stock, and Hollywood came calling at age ten. Her mother rejected the advances, saying she wanted her to be an actress, not a child star. Owen started auditioning for roles at the age of 15, using the name "Gloria Jane Owen". She found that as soon as people knew who her mother was, they expected her to be as accomplished an actress as her. She used a pseudonym to audition under, choosing Pamela (from a British book) and Britton (to emphasize the source).
Theatre work.
After a stint touring with bandleader Don McGuire, Britton's big break came when she was cast as both Celeste Holm's understudy and as Gertie in the Broadway production of "Oklahoma!". She played Meg Brockie in the Broadway production of "Brigadoon" (1947). When "Oklahoma!" went on tour, she took over Holm's role as Ado Annie.
Britton's New York agent eventually sent her credentials to Metro-Goldwyn-Mayer executive Marvin Schneck. He came to see one of her performances in Chicago, and was disappointed. He returned a second night, however, after additional cajoling from her agent, and he signed Britton immediately.
Hollywood.
Britton's first role in a major production was as Frank Sinatra's girlfriend in "Anchors Aweigh". Afterward, however, came a forgettable part in "A Letter for Evie" in 1946. She went on hiatus to play the comic role of "Meg Brockie" in the original 1947 production of "Brigadoon" on Broadway.
She returned to the big screen opposite Clark Gable in "Key to the City" (1950), and then went on to make her most significant film appearance in the classic "D.O.A.", also in 1950. She made her third film of the year in the Red Skelton vehicle, "Watch the Birdie" (1951). It was 19 years before she returned to the big screen.
Britton portrayed the title role of the TV version of the Chic Young newspaper comic strip "Blondie" (1957), opposite Arthur Lake as her husband, "Dagwood Bumstead".
Britton was married on April 8, 1943, in Texas, to Captain Arthur Steel after they met on a blind date arranged by one of her sisters. After the wedding, he was posted to Italy on active service while Britton remained working at home. They had a daughter, Katherine Lee, born on September 8, 1946. After the war, Steel worked as an advertising executive and went on to manage the Gene Autry hotels (Steel and Autry were first cousins). As their daughter grew up, Britton worked mainly in West Coast theater. She reprised her role in "Brigadoon" in 1954; appeared in "Annie Get Your Gun" at the Santa Barbara Bowl; and then returned to Broadway to replace an ailing Janis Paige in "Guys and Dolls".
"My Favorite Martian".
What is perhaps her signature role began in 1963 and lasted until 1966 when she appeared as the nosy and ditzy landlady, Mrs. Lorelei Brown, in "My Favorite Martian". After the series ended, Britton appeared in the movies, "If It's Tuesday, This Must Be Belgium" and "Suppose They Gave a War and Nobody Came".
Death.
In May 1974, while performing on tour with Don Knotts in "The Mind with the Dirty Man", Britton began to have headaches. She was diagnosed with a brain tumor and succumbed within weeks. Britton died in Arlington Heights, Illinois, on June 17, 1974. She was 51. Britton is buried at Forest Lawn Memorial Park in the Hollywood Hills.


Sacral splanchnic nerves

Sacral splanchnic nerves are splanchnic nerves that connect the inferior hypogastric plexus to the sympathetic trunk in the pelvis.
Structure.
The sacral sympathetic nerves arise from the sacral part of the sympathetic trunk, emerging anteriorly from the ganglia. They travel to their corresponding side's inferior hypogastric plexus, where the preganglionic nerve fibers synapse with the postganglionic sympathetic neurons, whose fibers ascend to the superior hypogastric plexus, the aortic plexus and the inferior mesenteric plexus, where they are distributed to the anal canal.
From the inferior hypogastric plexus, they also innervate pelvic organs and vessels.
The sacral sympathetic nerves contain a mix of preganglionic and postganglionic sympathetic fibers, but mostly preganglionic. They also contain general visceral afferent fibers. They are found in the same region as the pelvic splanchnic nerves, which arise from the sacral spinal nerves to provide parasympathetic fibers to the inferior hypogastric plexus.


International Journal of Neuroscience

The International Journal of Neuroscience is a peer-reviewed scientific journal that publishes original research articles, reviews, brief scientific notes, case studies, letters to the editor, and book reviews concerned with all aspects of neuroscience and neurology.
Editors.
The Editors-in-Chief of the "International Journal of Neuroscience" is Dr. Mohamad Bydon.


Inferior ganglion of vagus nerve

The inferior ganglion of the vagus nerve, (nodose ganglion) is a sensory ganglion of the peripheral nervous system. It is located within the jugular foramen where the vagus nerve exits the skull. It is larger than and below the superior ganglion of the vagus nerve.
Structure.
The neurons in the inferior ganglion of the vagus nerve are pseudounipolar and provide sensory innervation (general somatic afferent and general visceral afferent). The axons of the neurons which innervate the taste buds of the epiglottis synapse in the rostral portion of the solitary nucleus (gustatory nucleus). The axons of the neurons which provide general sensory information synapse in the spinal trigeminal nucleus. The axons of the neurons which innervate the aortic bodies, aortic arch, respiratory and gastrointestinal tract, synapse in the caudal part of the solitary nucleus.
Function.
The neurons in the inferior ganglion of the vagus nerve innervate the taste buds on the epiglottis, the chemoreceptors of the aortic bodies and baroreceptors in the aortic arch. Most importantly, the majority of neurons in the inferior ganglion provide sensory innervation to the heart, respiratory and gastrointestinal tracts and other abdominal organs as the urinary bladder.
Development.
The neurons in the inferior ganglion of the vagus nerve are embryonically derived from epibranchial neurogenic placodes.


Tuba

The tuba (; ) is the lowest-pitched musical instrument in the brass family. As with all brass instruments, the sound is produced by lip vibration, or a buzz, into a mouthpiece. It first appeared in the mid-19th century, making it one of the newer instruments in the modern orchestra and concert band. The tuba largely replaced the ophicleide. "Tuba" is Latin for "trumpet".
A person who plays the tuba is called a tubaist or tubist, or simply a tuba player. In a British brass band or military band, they are known as bass players.
History.
Prussian Patent No. 19 was granted to Wilhelm Friedrich Wieprecht and Johann Gottfried Moritz (1777–1840) on September 12, 1835 for a "bass tuba" in F1. The original Wieprecht and Moritz instrument used five valves of the Berlinerpumpen type that were the forerunners of the modern piston valve. The first tenor tuba was invented in 1838 by Carl Wilhelm Moritz (1810–1855), son of Johann Gottfried Moritz.
The addition of valves made it possible to play low in the harmonic series of the instrument and still have a complete selection of notes. Prior to the invention of valves, brass instruments were limited to notes in the harmonic series, and were thus generally played very high with respect to their fundamental pitch. Harmonics starting three octaves above the fundamental pitch are about a whole step apart, making a useful variety of notes possible.
The ophicleide used a bowl-shaped brass instrument mouthpiece but employed keys and tone holes similar to those of a modern saxophone. Another forerunner to the tuba was the serpent, a bass instrument that was shaped in a wavy form to make the tone holes accessible to the player. Tone holes changed the pitch by providing an intentional leak in the bugle of the instrument. While this changed the pitch, it also had a pronounced effect on the timbre. By using valves to adjust the length of the bugle the tuba produced a smoother tone that eventually led to its popularity. These popular instruments were mostly written for by French composers, especially Hector Berlioz. Berlioz famously wrote for the ophicleide in his compositions "Symphonie fantastique" and "Benvenuto Cellini (opera)". These pieces are now normally performed on F or CC tuba.
Adolphe Sax, like Wieprecht, was interested in marketing systems of instruments from soprano to bass, and developed a series of brass instruments known as saxhorns. The instruments developed by Sax were generally pitched in E and B, while the Wieprecht "basstuba" and the subsequent Cerveny contrabass tuba were pitched in F and C (see below on pitch systems). Sax's instruments gained dominance in France, and later in Britain and America, as a result of the popularity and movements of instrument makers such as Gustave Auguste Besson (who moved from France to Britain) and Henry Distin (who eventually found his way to America).
The cimbasso is also seen instead of a tuba in the orchestral repertoire. The name is translated from "corno in basso" in German. The original design was inspired by the ophicleide and bassoon. It is rare to see the cimbasso performed today, but are still around and used in historically accurate performances.
Role.
An orchestra usually has a single tuba, though an additional tuba may be requested. It serves as the bass of the orchestral brass section and it can reinforce the bass voices of the strings and woodwinds. It provides the bass of brass quintets and choirs (though many small brass ensembles will use the euphonium or bass trombone as the lowest voice). It is the principal bass instrument in concert bands, brass bands and military bands, and those ensembles generally have two to four tubas. It is also a solo instrument.
Tubas are used in marching bands, drum and bugle corps and in many jazz bands (see below). In British style brass bands, two E and two B tubas are used and are referred to as "basses".
Well known and influential parts for the tuba include:
Concertos have been written for the tuba by many notable composers, including Ralph Vaughan Williams (Tuba Concerto), Edward Gregson, John Williams, Alexander Arutiunian, Eric Ewazen, James Barnes, Joseph Hallman, Martin Ellerby, Philip Sparke, Kalevi Aho, Josef Tal, Bruce Broughton (Tuba Concerto), John Golland, Roger Steptoe and David Carlson.
Types and construction.
Tubas are found in various pitches, most commonly in F, E, C, or B. The main tube of a B tuba is approximately long, while that of a C tuba is , of an E tuba , and of an F tuba . The instrument has a conical bore, meaning the bore diameter increases as a function of the tubing length from the mouthpiece to the bell. The conical bore causes the instrument to produce a preponderance of even-order harmonics.
A tuba with its tubing wrapped for placing the instrument on the player's lap is usually called a concert tuba or simply a tuba. Tubas with the bell pointing forward ("pavillon tournant") instead of upward are often called "recording tubas" because of their popularity in the early days of recorded music, as their sound could more easily be directed at the recording microphone. When wrapped to surround the body for cavalry bands on horseback or marching, it is traditionally known as a helicon. The modern sousaphone, named after American bandmaster John Philip Sousa, resembles a helicon with the bell pointed up (in the original models as the J. W. Pepper prototype and Sousa's concert instruments) and then curved to point forward (as developed by Conn and others). Some ancestors of the tuba, such as the military "bombardon", had unusual valve and bore arrangements compared to modern tubas.
During the American Civil War, most brass bands used a branch of the brass family known as "saxhorns", which, by today's standards, have a narrower bore taper than tuba—the same as true cornets and baritones, but distinct from trumpets, euphoniums, and others with different tapers or no taper. Around the start of the Civil War, saxhorns manufactured for military use in the USA were commonly wrapped with the bell pointing backwards over the player's shoulder, and these were known as "over-the-shoulder saxhorns", and came in sizes from cornets down to E basses. However, the E bass, even though it shared the same tube length as a modern E tuba, has a narrower bore and as such cannot be called by the name "tuba" except as a convenience when comparing it to other sizes of the Saxhorn.
Most music for the tuba is written in bass clef in concert pitch, so tuba players must know the correct fingerings for their specific instruments. Traditional British-style brass band parts for the tuba are usually written in treble clef, with the B tuba sounding two octaves and one step below and the E tuba sounding one octave and a major sixth below the written pitch. This allows musicians to change instruments without learning new fingerings for the same written music. Consequently, when its music is written in treble clef, the tuba is a transposing instrument, but not when the music is in bass clef.
The lowest pitched tubas are the contrabass tubas, pitched in C or B, referred to as CC and BB tubas respectively, based on a traditional distortion of a now-obsolete octave naming convention. The fundamental pitch of a CC tuba is 32 Hz, and for a BB tuba, 29 Hz. The CC tuba is used as an orchestral, and concert band instrument in the U.S., but BB tubas are the contrabass tuba of choice in German, Austrian, and Russian orchestras. In the United States, the BB tuba is the most common in schools (largely due to the use of BB sousaphones in high school marching bands) and for adult amateurs. Many professionals in the U.S. play CC tubas, with BB also common, and many train in the use of all four pitches of tubas.
The next smaller tubas are the bass tubas, pitched in F or E (a fourth above the contrabass tubas). The E tuba often plays an octave above the contrabass tubas in brass bands, and the F tuba is commonly used by professional players as a solo instrument and, in America, to play higher parts in the classical repertoire (or parts that were originally written for the F tuba, as is the case with Berlioz). In most of Europe, the F tuba is the standard orchestral instrument, supplemented by the CC or BB only when the extra weight is desired. Wagner, for example, specifically notates the low tuba parts for "Kontrabasstuba," which are played on CC or BB tubas in most regions. In the United Kingdom, the E is the standard orchestral tuba.
The euphonium is sometimes referred to as a tenor tuba and is pitched in B, one octave higher than the BB contrabass tuba. The term "tenor tuba" is often used more specifically to refer to B rotary-valved tubas pitched in the same octave as euphoniums. The "Small Swiss Tuba in C" is a tenor tuba pitched in C, and provided with 6 valves to make the lower notes in the orchestral repertoire possible. The French C tuba was the standard instrument in French orchestras until overtaken by F and C tubas since the Second World War. One popular example of the use of the French C tuba is the "Bydło" movement in Ravel's orchestration of Mussorgsky's "Pictures at an Exhibition", though the rest of the work is scored for this instrument as well.
Larger BBB subcontrabass tubas exist, but are extremely rare (there are at least four known examples). The first two were built by Gustave Besson in BBB, one octave below the BB Contrabass tuba, on the suggestion of John Philip Sousa. The monster instruments were not completed until just after Sousa's death. Later, in the 1950s, British musician Gerard Hoffnung commissioned the London firm of Paxman to create a subcontrabass tuba in EEE for use in his comedic music festivals. Also, a tuba pitched in FFF was made in Kraslice by Bohland & Fuchs probably during 1910 or 1911 and was destined for the World Exhibition in New York in 1913. Two players are needed; one to operate the valves and one to blow into the mouthpiece.
Size vs. pitch.
In addition to the length of the instrument, which dictates the fundamental pitch, tubas also vary in overall width of the tubing sections. Tuba sizes are usually denoted by a quarter system, with designating a normal, full-size tuba. Larger rotary instruments are known as "kaisertubas" and are often denoted . Larger piston tubas, particularly those with front action, are sometimes known as "grand orchestral tubas" (examples: the Conn 36J Orchestra Grand Bass from the 1930s, and the current model Hirsbrunner HB-50 "Grand Orchestral", which is a replica of the large York tubas owned by the Chicago Symphony Orchestra). Grand orchestral tubas are generally described as tubas. Smaller instruments may be described as instruments. No standards exist for these designations, and their use is up to manufacturers who usually use them to distinguish among the instruments in their own product line. The size designation is related to the larger outer branches, and not to the bore of the tubing at the valves, though the bore is usually reported in instrument specifications. The quarter system is also not directly related to bell size, though there is typically a correlation. tubas are common in American grade schools for use by young tuba players for whom a full size instrument might be too cumbersome. Though smaller and lighter, they are tuned and keyed identically to full-size tubas of the same pitch, although they usually have 3 rather than 4 or 5 valves.
Valves.
Tubas are made with either piston or rotary valves. Rotary valves, invented by Joseph Riedl, are based on a design included in the original valve patents by Friedrich Blühmel and Heinrich Stölzel in 1818. Červeny of Graslitz was the first to use true rotary valves, starting in the 1840s or 1850s. Modern piston valves were developed by François Périnet for the saxhorn family of instruments promoted by Adolphe Sax around the same time. Pistons may either be oriented to point to the top of the instrument (top-action, as pictured in the figure at the top of the article) or out the front of the instrument (front-action or side-action). There are advantages and disadvantages to each valve style, but assertions concerning sound, speed, and clarity are difficult to quantify. German players generally prefer rotary valves while British and American players favor piston valves; the choice of valve type remains up to the performer.
Piston valves require more maintenance than rotary valves – they require regular oiling to keep them freely operating, while rotary valves are sealed and seldom require oiling. Piston valves are easy to disassemble and re-assemble, while rotary valve disassembly and re-assembly is much more difficult and is generally left to qualified instrument repair persons.
Tubas generally have from three to six valves, though some rare exceptions exist. Three-valve tubas are generally the least expensive and are almost exclusively used by amateurs, and the sousaphone (a marching version of a BB tuba) almost always has three valves. Among advanced players, four and five valve tubas are by far the most common choices, with six-valve tubas being relatively rare except among F tubas, which mostly have five or six valves.
The valves add tubing to the main tube of the instrument, thus lowering its fundamental pitch. The first valve lowers the pitch by a whole step (two semitones), the second valve by a semitone, and the third valve by three semitones. Used in combination, the valve tubing is too short and the resulting pitch tends to be sharp. For example, a BB tuba becomes (in effect) an A tuba when the first valve is depressed. The third valve is long enough to lower the pitch of a BB tuba by three semitones, but it is not long enough to lower the pitch of an A tuba by three semitones. Thus, the first and third valves used in combination lower the pitch by something "just short" of five semitones, and the first three valves used in combination are nearly a quarter tone sharp.
The fourth valve is used in place of combinations of the first and third valves, and the second and fourth used in combination are used in place of the first three valves in combination. The fourth valve can be tuned to lower the pitch of the main tube accurately by five semitones, and thus its use corrects the main problem of combinations being too sharp. By using the fourth valve by itself to replace the first and third combination, or the fourth and second valves in place of the first, second and third valve combinations, the notes requiring these fingerings are more in tune. The fourth valve used in combination with, rather than instead of, the first three valves fills in the missing notes in the bottom octave allowing the player to play chromatically down to the fundamental pitch of the instrument. For the reason given in the preceding paragraph some of these notes will tend to be sharp and must by "lipped" into tune by the player.
A fifth and sixth valve, if fitted, are used to provide alternative fingering possibilities to improve intonation, and are also used to reach into the low register of the instrument where all the valves will be used in combination to fill the first octave between the fundamental pitch and the next available note on the open tube. The fifth and sixth valves also give the musician the ability to trill more smoothly or to use alternative fingerings for ease of playing. This type of tuba is what is most found in orchestras and wind bands around the world.
The bass tuba in F is pitched a fifth above the BB tuba and a fourth above the CC tuba, so it needs additional tubing length beyond that provided by four valves to play securely down to a low F as required in much tuba music. The fifth valve is commonly tuned to a flat whole step, so that when used with the fourth valve, it gives an in-tune low B. The sixth valve is commonly tuned as a flat half step, allowing the F tuba to play low G as 1-4-5-6 and low G as 1-2-4-5-6. In CC tubas with five valves, the fifth valve may be tuned as a flat whole step or as a minor third depending on the instrument.
Compensating valves.
Some tubas have a compensating system to allow accurate tuning when using several valves in combination, simplifying fingering and removing the need to constantly adjust slide positions. The most popular of the automatic compensation systems was invented by Blaikley (Bevan, 1874) and was patented by Boosey (later, Boosey and Hawkes, which also, later still, produced Besson instruments). The patent on the system limited its application outside of Britain, and to this day tubas with compensating valves are primarily popular in the United Kingdom and countries of the former British Empire. The Blaikley design plumbs the instrument so that if the fourth valve is used, the air is sent back through a second set of branches in the first three valves to compensate for the combination of valves. This does have the disadvantage of making the instrument significantly more "stuffy" or resistant to air flow when compared to a non-compensating tuba. This is due to the need for the air to flow through the valves twice. It also makes the instrument heavier. But many prefer this approach to additional valves or to manipulation of tuning slides while playing to achieve improved intonation within an ensemble. Most modern professional-grade euphoniums also now feature Blaikley-style compensating valves.
Resonance and false tones.
Some tubas have a strong and useful resonance that is not in the well-known harmonic series. For example, most large B tubas have a strong resonance at low E (E1, 39 Hz), which is between the fundamental and the second harmonic (an octave higher than the fundamental). These alternative resonances are often known as false tones or privileged tones. Adding the six semitones provided by the three valves, these alternative resonances let the instrument play chromatically down to the fundamental of the open bugle (which is a 29 Hz B0). The addition of valves below that note can lower the instrument a further six semitones to a 20 Hz E0. Thus, even three-valved instruments with good alternative resonances can produce very low sounds in the hands of skilled players; instruments with four valves can play even lower. The lowest note in the widely known repertoire is a 16 Hz double-pedal C0 in the William Kraft piece "Encounters II", which is often played using a timed flutter tongue rather than by buzzing the lips. The fundamental of this pitch borders on infrasound and its overtones define the pitch in the listener's ear.
The most convincing explanation for false tones is that the horn is acting as a "third of a pipe" rather than as a half-pipe. The bell remains an anti-node, but there would then be a node one-third of the way back to the mouthpiece. If so, it seems that the fundamental would be missing entirely, and would only be inferred from the overtones. However, the node and the antinode collide in the same spot and cancel out the fundamental.
Materials and finish.
The tuba is generally constructed of brass, which is either unfinished, lacquered or electro-plated with nickel, gold or silver. Unfinished brass will eventually tarnish and thus must be periodically polished to maintain its appearance.
Manufacturers.
There are many types of tubas that are manufactured in Europe, the United States, and Asia. In Europe, the predominant models that are professionally used are Meinl-Weston (Germany) and Miraphone (Germany). Asian brands include the Yamaha Corporation (Japan) and Jupiter Instruments (Taiwan). Holton Instrument Company and King Musical Instruments are the some of the most well known brands from the United States.
Variations.
Some tubas are capable of being converted into a marching style, known as "marching tubas". A leadpipe can be manually screwed on next to the valves. The tuba is then usually rested on the left shoulder (although some tubas allow use of the right shoulder), with the bell facing directly in front of the player. Some marching tubas are made only for marching, and cannot be converted into a concert model. Most marching bands opt for the sousaphone, an instrument that is easier to carry since it was invented specifically for this and almost always cheaper than a true marching tuba. The earlier helicon is still used by bands in Europe and other parts of the world. Drum and bugle corps players, however, generally use marching tubas or Contrabass bugles. Standard tubas can also be played whilst standing. With the comfort of the player in mind, companies have provided harnesses that sometimes use a strap joined to the tuba with two rings, a 'sack' to hold the bottom of the tuba, or numerous straps holding the larger parts of tubing on the tuba. The strap(s) goes over the shoulder like a sash or sit at the waist, so the musician can play the instrument in the same position as when sitting.
Jazz.
The tuba has been used in jazz since the genre's inception. In the earliest years, bands often used a tuba for outdoor playing and a double bass for indoor performances. In this context, the tuba was sometimes called "brass bass", as opposed to the double bass "(string bass)". Many musicians played both instruments.
This practice was mostly used in the New Orleans jazz scene. The tuba was used most frequently with the Louis Armstrong groups and prominent in the album "Hot Five".
In modern jazz, it is not unknown for their players to take solos. New Orleans style brass bands like the Dirty Dozen Brass Band and the Rebirth Brass Band use a sousaphone as the bass instrument. Bill Barber played tuba on several Miles Davis albums, including the sessions compiled as the "Birth of the Cool" and "Miles Ahead". New York City-based tubist Marcus Rojas performed frequently with Henry Threadgill. Starting in 1955, Stan Kenton made his fifth trombonist double on tuba, namely on ballads to make use of the tuba's distinct warm, enveloping sound.


Disuse supersensitivity

Disuse supersensitivity, also pharmacological disuse supersensitivity or pharmacological denervation supersensitivity, is the increased sensitivity by a postsynaptic cell because of decreased input by incoming axons, e.g., due to the exposure to an antagonist drug.
Jaffe and Sharpless pointed out that withdrawal syndrome after the cessation of a chronically-used drug often shows an exaggerated response which is normally suppressed by the drug which produced a dependence. They suggested the model according to which a drug has both excitatory and depressive effects. Depressive effects generate hypersensitivity, but at the same time they mask it. When drug usage stops, hypersensitivity becomes unmasked.


Methestrol

Methestrol (; brand name Meprane) or methoestrol, also known as promethestrol or promethoestrol () or as dimethylhexestrol, is a synthetic nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol which is no longer marketed.
A related drug is methestrol dipropionate (or promethestrol dipropionate) (brand name Meprane Dipropionate).


Pyrrolizidine alkaloid sequestration

Pyrrolizidine alkaloid sequestration by insects is a strategy to facilitate defense and mating. Various species of insects have been known to utilize molecular compounds from plants for their own defense and even as their pheromones or precursors to their pheromones. A few Lepidoptera have been found to sequester chemicals from plants which they retain throughout their life and some members of Erebidae are examples of this phenomenon. Starting in the mid-twentieth century researchers investigated various members of Arctiidae, and how these insects sequester pyrrolizidine alkaloids (PAs) during their life stages, and utilize these chemicals as adults for pheromones or pheromone precursors. PAs are also used by members of the Arctiidae for defense against predators throughout the life of the insect.
Overview.
Pyrrolizidine alkaloids are a group of chemicals produced by plants as secondary metabolites, all of which contain a pyrrolizidine nucleus. This nucleus is made up of two pyrrole rings bonded by one carbon and one nitrogen. There are two forms in which PAs can exist and will readily interchange between: a pro-toxic free base form, also called a tertiary amine, or in a non-toxic form of N-oxide.
Researchers have collected data that strongly suggests that PAs can be registered by taste receptors of predators, acting as a deterrent from being ingested. Taste receptors are also used by the various moth species that sequester PAs, which often stimulates them to feed. As of 2005, all of the PA sequestering insects that have been studied have all evolved a system to keep concentrations of the PA pro-toxic form low within the insect's tissues.
Researchers have found a number of Arctiidae that utilize PAs for protection and for male pheromones or precursors of the male pheromones, and some studies have found evidence suggesting PAs have behavioral and developmental effects. "Estigmene acrea", "Cosmosoma myrodora", "Utetheisa ornatrix", "Creatonotos gangis" and "Creatonotos transiens" are all members of the family Arctiidae and found to use PAs for their defense and/or male pheromones. Parsimony suggests that the sequestering of PAs in the larval stage evolved in the subfamily Arctiinae common ancestor. The loss of ability to sequester and utilize PAs has occurred in a number of species, along with the switch from larval uptake to adult uptake of PAs occurring multiple times within the Arctiinae taxon.
Members of Arctiidae typically sequester PAs from their diets, but sometimes must specifically ingest fluids excreted by plants that are not a part of their diets. Sequestered PAs are kept in various tissues and varying concentration which is dependent upon the species. PAs are found in the cuticle of all studied Arctiidae mentioned here, but some also package these chemicals into their spermatophores as seen in "Creatonotos gangis" and "Creatonotos transiens". The display of PAs on the exoskeleton is believed to cue predators to the unpalatability of the prey.
Eisner and Eisner looked at the palatability of PA positive and negative "U. ornatrix" to wolf spiders, "Lycosa ceratiola", in both the larval form and adult form. They found that the pyrrolizidine-positive organisms were typically released unharmed by spiders except in two field circumstances where the larvae were probably envenomated prior to the spider's release and died two days after the attack. All of the PA-negative organisms were eaten by spiders. These findings were in line with prior studies done by Eisner and Meinwald which looked at orb weavers and "U. ornatrix", along with spiders being fed beetle larva covered in PAs, which they rejected. All of these findings support PAs being utilized for defense against predation.
Studies have further elucidated the defenses and uses of PAs in Arctiidae. One study researched "C. myrodora" and how PAs protect this species from spider predation among other things. It found that PAs ingested from fluids excreted by plants aided in defense from predation. All organisms permitted access to PA-containing diets that were fed to spiders were cut loose from the webs. Females that had PA-deprived diets, but were allowed to mate with PA-positive males, were also released from the spider's webs. Further observations showed that male "C. myrodora" have a pair of pouches where they produce PA-laden filaments, which are typically released over the female prior to copulation as a nuptial gift. Experiments show that the filaments give the females more PAs, explaining why spiders released mated PA-negative females from their webs. Most of the PAs from the males were subsequently transferred to the eggs when deposited. Three clusters of eggs that were laid after copulation with a PA-positive male all tested positive for alkaloids and the one cluster that resulted from a PA-negative male copulation tested negative. By the eggs getting a dose of PAs, the authors suggest that the eggs are being protected from predators such as Coccinellidae beetles.
Jordan and others’ study found a very interesting effect of the larval ingestion of PAs. Male "Estigmene acrea" moths that consumed PAs in their diet as larvae produced hydroxydanaidal, a volatile PA compound, and displayed their coremata: a bifid, inflatable male-specific organ, utilized in dispersing pheromones in the adult stage. Larvae that were fed diets without PAs rarely displayed their coremata and did not produce hydroxydanaidal. E. acrea have been observed in the wild displaying their coremata, an activity which attracts both males and females and is known as "lekking". Lekking was described by Willis and Birch in 1982, but larvae raised in the laboratory prior to this study rarely engaged in lekking or corematal displays. Scientists were unsure of why this phenomenon didn't occur in the lab, but laboratory raised larvae were usually reared on commercially available food which lacks PAs. The authors suggest that the PAs are used by the males to attract other moths by releasing the volatile PA hydroxydanaidal into the air. It is suggested in this study that this strategy of mate attraction came about by tapping into the PA affinity already programmed into the moths for feeding, which is further supported by the observation that E. acrea females release their pheromones a little bit later in the evening than the males.
Similar uses of coremata to attract other moths have been observed in "C. gangis" and "C. transiens" along with altered development of coremata when larvae are reared without PAs. Boppre and Schneider observed adult males of these two species that were not permitted to eat PAs. Their coremata only developed into two, stalk-like projections with very few hairs arising from these stalks. Males that were given plants that produced PAs to feed upon, developed long coremata with four tubes, each longer than the males body, and each tube was highly pubescent. The authors suggest from this observation that there is a basic corematal phenotype, the two stalked coremata, and that PAs are required to form full coremata which is much larger and more elaborate than the basic corematal expression. These observations were further investigated by feeding larvae different amounts of PAs which had a direct correlation to the development of the coremata, which reached a maximum plateau around 2 mg of PAs ingested while in larval form. Similar to Jordan and others’ findings, the males raised on a diet devoid of PAs did not produce hydroxydanaidal.


Axoplasm

Axoplasm is the cytoplasm within the axon of a neuron (nerve cell). For some neuronal types this can be more than 99% of the total cytoplasm.
Axoplasm has a different composition of organelles and other materials than that found in the neuron's cell body (soma) or dendrites. In axonal transport (also known as axoplasmic transport) materials are carried through the axoplasm to or from the soma.
The electrical resistance of the axoplasm, called axoplasmic resistance, is one aspect of a neuron's cable properties, because it affects the rate of travel of an action potential down an axon. If the axoplasm contains many molecules that are not electrically conductive, it will slow the travel of the potential because it will cause more ions to flow across the axolemma (the axon's membrane) than through the axoplasm.
Structure.
Axoplasm is composed of various organelles and cytoskeletal elements. The axoplasm contains a high concentration of elongated mitochondria, microfilaments, and microtubules. Axoplasm lacks much of the cellular machinery (ribosomes and nucleus) required to transcribe and translate complex proteins. As a result, most enzymes and large proteins are transported from the soma through the axoplasm. Axonal transport occurs either by fast or slow transport. Fast transport involves vesicular contents (like organelles) being moved along microtubules by motor proteins at a rate of 50–400mm per day. Slow axoplasmic transport involves the movement of cytosolic soluble proteins and cytoskeletal elements at a much slower rate of 0.02-0.1mm/d. The precise mechanism of slow axonal transport remains unknown but recent studies have proposed that it may function by means of transient association with the fast axonal transport vesicles. Though axonal transport is responsible for most organelles and complex proteins present in the axoplasm, recent studies have shown that some translation does occur in axoplasm. This axoplasmic translation is possible due to the presence of localized translationally silent mRNA and ribonuclear protein complexes.
Function.
Signal transduction.
Axoplasm is integral to the overall function of neurons in propagating action potential through the axon. The amount of axoplasm in the axon is important to the cable like properties of the axon in cable theory. In regards to cable theory, the axoplasmic content determines the resistance of the axon to a potential change. The composing cytoskeletal elements of axoplasm, neural filaments, and microtubules provide the framework for axonal transport which allows for neurotransmitters to reach the synapse. Furthermore, axoplasm contains the pre-synaptic vesicles of neurotransmitter which are eventually released into the synaptic cleft.
Damage detection and regeneration.
Axoplasm contains both the mRNA and ribonuclearprotein required for axonal protein synthesis. Axonal protein synthesis has been shown to be integral in both neural regeneration and in localized responses to axon damage. When an axon is damaged, both axonal translation and retrograde axonal transport are required to propagate a signal to the soma that the cell is damaged.
History.
Axoplasm was not a main focus for neurological research until many years of learning of the functions and properties of squid giant axons. Axons in general were very difficult to study due to their narrow structure and in close proximity to glial cells. To solve this problem squid axons were used as an animal model due to the relatively vast sized axons compared to humans or other mammals. These axons were mainly studied to understand action potential, and axoplasm was soon understood to be important in membrane potential. The axoplasm was at first just thought to be very similar to cytoplasm, but axoplasm plays an important role in transference of nutrients and electrical potential that is generated by neurons.
It actually proves quite difficult to isolate axons from the myelin that surrounds it, so the squid giant axon is the focus for many studies that touch on axoplasm. As more knowledge formed from studying the signalling that occurs in neurons, transfer of nutrients and materials became an important topic to research. The mechanisms for the proliferation and sustained electrical potentials were affected by the fast axonal transport system. The fast axonal transport system uses the axoplasm for movement, and contains many non-conductive molecules that change the rate of these electrical potentials across the axon, but the opposite influence does not occur. The fast axonal transport system is able to function without an axolemma, implying that the electrical potential does not influence the transport of materials through the axon. This understanding of the relationship of axoplasm regarding transport and electrical potential is critical in the understanding of the overall brain functions.
With this knowledge, axoplasm has become a model for studying varying cell signaling and functions for the research of neurological diseases like Alzheimer's, and Huntington's. Fast axonal transport is a crucial mechanism when examining these diseases and determining how a lack of materials and nutrients can influence the progression of neurological disorders.


The Signal (2007 film)

The Signal is a 2007 American horror film written and directed by independent filmmakers David Bruckner, Dan Bush and Jacob Gentry. It is told in three parts, in which all telecommunication and audiovisual devices transmit only a mysterious signal turning people mad and activating murderous behaviour in many of those affected.
The film's three interconnected chapters ("transmissions") are presented in a nonlinear narrative. Each of them manifests elements of (besides the overall genre of psychological horror), respectively, splatter film, black comedy, and a post-apocalyptic love story. "The Signal" was met with a mixed but largely positive critical reception.
Plot.
The film opens, showing that Mya is cheating on her husband Lewis with a man named Ben. Ben attempts to convince Mya to leave the city with him, but she remains noncommittal. As Mya exits, Ben turns the television on and watches a bizarre, psychedelic sequence of images. Mya begins to listen to a compact disc given to her by Ben, but she is menaced by men who are acting strangely in a parking garage. When she reaches her apartment building, she finds more people behaving strangely. Unknown to Mya, the Signal, a static-like interference that is coming through the television, radio and telephone amplifies each person's negative emotional traits, causing them to act irrationally and, in most cases, violently.
Transmission 1: Crazy in Love.
Written and directed by David Bruckner.
Once inside her apartment, Lewis and two friends, Jerry and Rod attempt to fix the TV, but Lewis, the first to react to the Signal, beats Jerry to death with a baseball bat over a minor argument. Mya flees in panic, leaving Rod and Lewis in a struggle, but finds the whole building in chaos with people killing each other. Mya hides out in the nearby apartment until morning. When she decides to leave and re-enter her home, she finds an unconscious Lewis, bound to a chair with duct-tape. He awakens only to see her leave him behind and exit into the hall listening to Ben's compact disc, but encounters Rod who drags her into a janitor's closet. He then tells her of the night he spent trying to survive in the apartment complex. It becomes evident that the Signal affects each person differently, and that there is the possibility that Rod is also crazy, though he seems to largely have control of his own judgment. Together, they escape, and attempt to drive to safety. But after being shot by a policewoman and almost left behind by Mya, Rod becomes even more violent and attacks Mya, who crashes the car. Rod is incapacitated and trapped in the vehicle, while Mya flees, telling a stranger named Clark that she is going to the train station.
Transmission 2: The Jealousy Monster.
Written and directed by Jacob Gentry.
The story turns to Ben, who finds the duct-taped Lewis and loosens his bonds. Lewis knocks Ben unconscious and puts him in the back of a pest control van. At a nearby apartment, a woman named Anna is setting up for a New Year party. The Signal has affected her so that her dutifulness as a homemaker is amplified (though she is also quite possibly made psychologically unstable from being forced to kill her own husband), and despite having killed her crazed husband in self-defense, she has continued planning for the party as if nothing has happened. Clark, who is her neighbor, and a conspiracy theorist, soon arrives. The two begin attempting to figure out what is happening, and Clark also admits that he has decapitated Rod with a shovel, when Rod attacked him after being freed from the car wreck. Eventually Lewis makes his way to the apartment, under the mistaken belief that Mya has been there, because her car is crashed outside. At first, Lewis befriends Anna and Clark, and they convince themselves that none of them have been affected by the Signal, and that they have to band together in order to survive. Lewis, whose violent and paranoid tendencies are clearly amplified by the Signal, kills Anna's niece, Laura, who arrives at the door seeking help, under the mistaken belief that she is attacking Anna with a knife. He dismisses the act as defense on the part of Anna, but Clark convinces him not to attack the next arrival, Jim, who is apparently oblivious of the situation. While Anna hallucinates that Clark is her husband, Lewis hallucinates that Jim is Ben, taunting him. He beats Jim to death, restrains Clark in a chair by staking his arms to the chair with kitchen knives, then attacks Anna, spraying her with insecticide until she is blind. Once he realizes she knows nothing about Mya's whereabouts, Lewis forces her to ingest the poison, apparently killing her. He then exposes Clark to the Signal in order to convince him to tell him where Mya had gone. Ben, having woken up and freed himself from Lewis's van, enters the apartment and attacks Lewis with the pesticide canister, knocking him out.
Transmission 3: Escape from Terminus.
Written and directed by Dan Bush.
Lewis wakes up and follows Ben and Clark. He attempts to kill them in a tool shed, but they fight him off and escape. After Ben convinces Clark that the Signal is a lie, thus breaking its effect on him, Clark informs Ben where Mya was headed. Ben and Clark make a run through the now mostly-dead city and arrive at the train station. There, they find Mya tied to a chair, being forced to watch the Signal by Lewis, who attacks them and strangles Clark until he is unconscious. Ben then resorts to using Lewis's own paranoia against him, eventually tricking Lewis into believing that their roles are reversed, and that Lewis is the one man he hates most: Mya's lover. Lewis punches a signal-broadcasting TV, in a frustrated rage, electrocuting himself.
The story ends ambiguously. A series of scenes showing Ben and Mya with Clark, stocking up on supplies, then Ben and Mya going separate ways from Clark, suggesting they have succeeded. However, the next scene reveals Mya still tied to the chair, seemingly catatonic due to her prolonged exposure to the Signal. Ben places Mya's headphones on her, and she closes her eyes, a tear rolling down her cheek, before the credits appear. Whether this is the final reality, or a flashback before Ben and Mya's escape from the city, is left for the viewer to decide.
Production and release.
"The Signal" was created by four filmmakers who have been collaborating since 1999 in Atlanta, Georgia and each of its chapters of which had different directors during shooting. The film was completed for the 2007 Sundance Film Festival on a budget of only $50,000 and shot over the course of 13 days. The film premiered January 22, 2007 at the Sundance Film Festival, where it was acquired by Magnolia Pictures, and released on DVD and Blu-ray on June 10, 2008.
After long delay due to the search for a song to replace an unlicensed cover of Lou Reed's "Perfect Day" by Jon Thomas Hall in the soundtrack, the film was theatrically released on February 22, 2008. The song finally used is a cover of Joy Division's "Atmosphere" by Ola Podrida. As a promotion for the film, a new short podcast was released bi-weekly through a horror film news site Bloody Disgusting. On February 23, 2008, it was reported that two men were stabbed by a stranger in a Fullerton, California movie theatre during a showing of "The Signal"; one of them suffered non life-threatening injuries to his arm, while the other suffered a lung puncture.
The home media release includes an audio commentary from the directors, deleted scenes, the making-of featurette, the complete short film "The Hap Hapgood Story" that was shown on TV in the introduction sequence of "The Signal", as well as three short (each around four-minute long) additional "transmissions" featuring entirely different new characters and locations ("Transmission 14: Technical Difficulties", "Transmission 23: The Return", and "Transmission 37: Crosstown Traffic" by Jacob Gentry). Gentry, who also directed the second part of the film, shared his bonus featurette on Vimeo.
Reception.
"The Signal" received 59% positive reviews at Rotten Tomatoes, with the website's consensus states, ""The Signal" is gruesome, funny, and has big thoughts about society, but those disparate elements fail to come together convincingly." Its average rating at Metacritic is 63/100 (generally favorable reviews). In 2012, "Total Film" included it on their list of the best independent horror films, noting that if "The Signal" had a bigger budget "it would have had more room to explore its big ideas."
In a review for "The Boston Globe", Wesley Morris wrote that while the film's episodes vary in their quality (he opined that the first is "by far the most impressive"), "the filmmaking stays sharp and the acting maintains its ferocity." On the other hand, Owen Gleiberman of "Entertainment Weekly" called it a poor mix of "Poltergeist", "Invasion of the Body Snatchers", "Re-Animator", "Shivers" and "Shaun of the Dead".
Karen Kemmerle of Tribeca Film recommended this "surreal, primal, unexpected and unsettling journey through a society gone mad", and stated that "the style of the film is reminiscent of those great 70s horror movies—it's raw, grainy and insanely visceral," and its raw and low budget feel "only draws to its appeal." According to Aaron Gillot of "Filmmaker", "for such a modest movie ... "The Signal" is creative, intelligent, and one of the few movies that truly immerses the viewer in the terror of madness. Any fan of horror should seek it out.


Glossary of Mafia-related words

This is a glossary of words related to the Mafia, primarily the Italian American Mafia and Sicilian Mafia.


Eddie Connolly

Eddie Connolly (29 October 1985 – 17 September 2015) was an Irish hurler. He played for his local club Loughmore-Castleiney and was a member of the Tipperary senior inter-county team.
On 13 March 2011, he made his senior debut for Tipperary against Offaly, starting at right corner back in the National Hurling League in a 1-20 to 0-10 victory.
Eddie was an accomplished defender in hurling and Gaelic football, playing senior hurling and football for the premier county. Eddie captained Tipperary to an All-Ireland Intermediate hurling championship in 2012. He was also a distinguished player for his college Dublin Institute of technology.
Connolly was diagnosed with brain cancer in 2013. He died on 17 September 2015 at the age of 29.


Intercalated nucleus

Intercalated nucleus ("nucleus intercalatus") called also Staderini nucleus is a group of nerve cells in the medulla oblongata, between the dorsal nucleus of the vagus nerve (lateral to the intercalated nucleus) and the nucleus of the hypoglossal nerve (medial to intercalated nucleus), forming part of the perihypoglossal nuclear complex.
Function. Probably involved in the control of the vestibuloocular reflex and may contribute to the vertical neural integrator.
Described for the first time in 1894 by Rutilio Staderini (1861–1942), Italian neuroanatomist
References.
John Alan Kiernan, Murray Llewellyn Barr. "Barr's The Human Nervous System: An Anatomical Viewpoint." 2008


Maurocalcine

Maurocalcine is a protein isolated from the venom of the scorpion "Maurus palmatus", which belongs to the family Chactidae. It was first reported by Fajloun "et al." in 2000.
It is 33 Amino acid residues in length, containing three disulphide bonds which folds into the inhibitor cystine knot motif. It acts by modifying the activity of the type 1 ryanodine receptor.


Tandamine

Tandamine is a selective norepinephrine reuptake inhibitor with a tricyclic structure. It was developed in the 1970s as an antidepressant but was never commercialized. Tandamine is analogous to pirandamine, which, instead, acts as a selective serotonin reuptake inhibitor (SSRI).


Source literature

Source literature (understood as printed texts) is a kind of information source. It might, for example, be cited and used as sources in academic writings, and then called the literature on the subject.
The meaning of "source literature" is relative. From the point of view of a bibliographic index the indexed papers are "source literature". For example, the "Social Sciences Citation Index" is a "source index" covering the journals being indexed. These journals are the source literature from the point of view of this index. But from the point of view of the indexed papers they are the bibliographical references contained in the single papers "source literature".
In the humanities, the term "source literature" has a more precise meaning than "published sources": Many archives, for example, publish important sources to be used by historians and other scholars as reliable editions of formerly unpublished sources. The publishing of such sources requires knowledge of text philology and other fields. But this kind of expertise put into the publishing of source literature should be differentiated from the kind of expertise needed in order to use the sources in, for example, historical research. A historian may or may not use such "source literature" and on the basis of his research publish a paper, which in the UNISIST model is considered primary literature.
Søndergaard, Andersen and Hjørland (2003) thus suggest that source literature is a distinct kind of literature to be distinguished from primary literature.


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