Neuromere

Neuromeres are morphologically or molecularly defined transient segments of the early developing brain. Rhombomeres are such segments that make up the rhombencephalon or hindbrain. More controversially, some argue that there exist early developmental segments that give rise to structures of the midbrain (mesomeres) and forebrain (prosomeres).
Neuromeres are the segments of the neural tube that establish the embryonic brain during development. They can then be divided up so that each is carrying different and unique genetic traits, expressing different features in development.
Neuromeres were first discovered in the beginning of the 20th century. Although researchers have long since recognized the different signs of differentiation during embryonic development, it was widely thought that neuromeres held no relation to the structure of the nervous system. Swedish neuroembyrologists Bergquist and Kallen clarified the role of neuromeres by conducting several studies showing that neuromeres are important in the development of the nervous system. These experiments consisted of studying the brains of different vertebrates during their development period.
During embryonic development, neural crest cells from each neuromere prompt the development of the nerves and arteries, helping to support the development of craniofacial tissues. If gene expression goes wrong, it can have severe effects on the developing embryo, causing abnormalities like craniofacial clefts, also known as cleft palates. The anatomical boundaries of neuromers are determined by the expression of unique genes known as Hox genes in a particular zone. The Hox genes contain the 183-bp homeobox, which encodes a particular portion of the Hox proteins called the homeodomain. The homeodomain can then bind to other portions of DNA to regulate gene expression. These genes determine the basic structure and orientation of an organism after the embryonic segments have formed. The neural crest cells that are found outside of a given neuromere will express the same proteins as the cells that are found inside the neural tube. The genes that are being expressed fall into two categories, extracellular signaling proteins and intracellular transcription factors. The genes are able to perform different tasks at different times depending on the environment that may or not be changing as well as when they are being activated and expressed.
The neural crest was first discovered by Wilhelm His in 1868 when he was studying the embryo of a chick. He first named it Zwischenstrang, which literally translated to mean “intermediate cord.” The name neural crest develops from the neural folds during embryonic development. This is where the neural plate folds in on itself, forming the neural crest. Neural crest cells will eventually become portions of the peripheral nervous system. During development, the neural tube will considered the precursore to the spinal cord and the rest of the nervous system, eventually becoming the Central Nervous System.
The central nervous system can be divided into three classes of neuromeres: prosomeres, mesomeres, and rhombomeres. The forebrain forms the six prosomers, p1 to p6, which are then divided into two more categories, dorsal and ventral. The telencephalon forms from the dorsal parts of p6 and p5, where p6 becomes the olfactory system and p5 will coincide with the visual system. Mesomeres, m1 and m2, become the midbrain, which contains the superior and inferior colliculi. The 12 rhombomeres, which are numbered from r0 to r11, construct the hindbrain. The myelencephalon is made from rhombomeres r2 to r11, which also form the medulla. These rhombomeres are also associated with the neural crest that supplies the pharyngeal arches, a set of visible tissues that are in line with the developing brain and give rise to the head and neck.
Spinal Cord Anatomy.
Spinal segments are the part of the spinal cord, from which ventral and dorsal roots exit to form a specific pair of spinal nerves.
The spinal chord is not segmented itself, it is only made into segments by the spinal nerves as they leave.
31 deferent segments exists in a human spinal cord:
8 cervical segments.
Cervical nerves exit above C1 segment and below C1-C7.
Note that this creates 8 nerves and segments corresponding to only 7 cervical vertebra.
12 thoracic segments.
Nerves exit below T1-T12.
5 lumbar segments.
Nerves exit below L1-L5.
5 sacral segments.
Nerves exit below S1-S5.
1 coccygeal segment.
Originally, during development there are two segments S1 and S2 which fuse.
The nerves in this case exit at the coccyx.
In more detail.
The spinal cord is the main pathway for information connecting the brain and peripheral nervous system. The length of the spinal cord is much shorter than the length of the bony spinal column. The human spinal cord extends from the foramen magnum and continues through to the conus medullaris near the second lumbar vertebra, terminating in a fibrous extension known as the filum terminale.
It is about 45 cm (18 in) long in men and around 43 cm (17 in) in women, ovoid-shaped, and is enlarged in the cervical and lumbar regions. The cervical enlargement, located from C3 to T2 spinal segments, is where sensory input comes from and motor output goes to the arms. The lumbar enlargement, located between L1 and S3 spinal segments, handles sensory input and motor output coming from and going to the legs.
The spinal cord is protected by three layers of tissue, called spinal meninges, that surround the canal. The dura mater is the outermost layer, and it forms a tough protective coating. Between the dura mater and the surrounding bone of the vertebrae is a space called the epidural space. The epidural space is filled with adipose tissue, and it contains a network of blood vessels. The arachnoid mater is the middle protective layer. Its name comes from the fact that the tissue has a spiderweb-like appearance. The space between the arachnoid and the underlying pia mater is called the subarachnoid space. The subarachnoid space contains cerebrospinal fluid (CSF). The medical procedure known as a lumbar puncture (or "spinal tap") involves use of a needle to withdraw cerebrospinal fluid from the subarachnoid space, usually from the lumbar region of the spine. The pia mater is the innermost protective layer. It is very delicate and it is tightly associated with the surface of the spinal cord. The cord is stabilized within the dura mater by the connecting denticulate ligaments, which extend from the enveloping pia mater laterally between the dorsal and ventral roots. The dural sac ends at the vertebral level of the second sacral vertebra.
In cross-section, the peripheral region of the cord contains neuronal white matter tracts containing sensory and motor neurons. Internal to this peripheral region is the gray, butterfly-shaped central region made up of nerve cell bodies. This central region surrounds the central canal, which is an anatomic extension of the spaces in the brain known as the ventricles and, like the ventricles, contains cerebrospinal fluid.
The spinal cord has a shape that is compressed dorso-ventrally, giving it an elliptical shape. The cord has grooves in the dorsal and ventral sides. The posterior median sulcus is the groove in the dorsal side, and the anterior median fissure is the groove in the ventral side.
In the upper part of the vertebral column, spinal nerves exit directly from the spinal cord, whereas in the lower part of the vertebral column nerves pass further down the column before exiting. The terminal portion of the spinal cord is called the conus medullaris. The pia mater continues as an extension called the filum terminale, which anchors the spinal cord to the coccyx. The cauda equina (“horse’s tail”) is the name for the collection of nerves in the vertebral column that continue to travel through the vertebral column below the conus medullaris. The cauda equina forms as a result of the fact that the spinal cord stops growing in length at about age four, even though the vertebral column continues to lengthen until adulthood. This results in the fact that sacral spinal nerves actually originate in the upper lumbar region. The spinal cord can be anatomically divided into 31 spinal segments based on the origins of the spinal nerves.
Each segment of the spinal cord is associated with a pair of ganglia, called dorsal root ganglia, which are situated just outside the spinal cord. These ganglia contain cell bodies of sensory neurons. Axons of these sensory neurons travel into the spinal cord via the dorsal roots.
Ventral roots consist of axons from motor neurons, which bring information to the periphery from cell bodies within the CNS. Dorsal roots and ventral roots come together and exit the intervertebral foramina as they become spinal nerves.
The gray matter, in the center of the cord, is shaped like a butterfly and consists of cell bodies of interneurons and motor neurons. It also consists of neuroglia cells and unmyelinated axons. Projections of the gray matter (the “wings”) are called horns. Together, the gray horns and the gray commissure form the “gray H.”
The white matter is located outside of the gray matter and consists almost totally of myelinated motor and sensory axons. “Columns” of white matter carry information either up or down the spinal cord.
Within the CNS, nerve cell bodies are generally organized into functional clusters, called nuclei. Axons within the CNS are grouped into tracts.
There are 33 spinal cord nerve segments in a human spinal cord:
8 cervical segments forming 8 pairs of cervical nerves (C1 spinal nerves exit spinal column between occiput and C1 vertebra; C2 nerves exit between posterior arch of C1 vertebra and lamina of C2 vertebra; C3-C8 spinal nerves through IVF above corresponding cervica vertebra, with the exception of C8 pair which exit via IVF between C7 and T1 vertebra)
12 thoracic segments forming 12 pairs of thoracic nerves (exit spinal column through IVF below corresponding vertebra T1-T12)
5 lumbar segments forming 5 pairs of lumbar nerves (exit spinal column through IVF, below corresponding vertebra L1-L5)
5 sacral segments forming 5 pairs of sacral nerves (exit spinal column through IVF, below corresponding vertebra S1-S5)
3 coccygeal segments joined up becoming a single segment forming 1 pair of coccygeal nerves (exit spinal column through the sacral hiatus).
In the fetus, vertebral segments correspond with spinal cord segments. However, because the vertebral column grows longer than the spinal cord, spinal cord segments do not correspond to vertebral segments in the adult, particularly in the lower spinal cord. For example, lumbar and sacral spinal cord segments are found between vertebral levels T9 and L2, and the spinal cord ends around the L1/L2 vertebral level, forming a structure known as the conus medullaris.
Although the spinal cord cell bodies end around the L1/L2 vertebral level, the spinal nerves for each segment exit at the level of the corresponding vertebra. For the nerves of the lower spinal cord, this means that they exit the vertebral column much lower (more caudally) than their roots. As these nerves travel from their respective roots to their point of exit from the vertebral column, the nerves of the lower spinal segments form a bundle called the cauda equina.
There are two regions where the spinal cord enlarges:
Cervical enlargement - corresponds roughly to the brachial plexus nerves, which innervate the upper limb. It includes spinal cord segments from about C4 to T1. The vertebral levels of the enlargement are roughly the same (C4 to T1).
Lumbosacral enlargement - corresponds to the lumbosacral plexus nerves, which innervate the lower limb. It comprises the spinal cord segments from L2 to S3 and is found about the vertebral levels of T9 to T12.
Embryology.
The spinal cord is made from part of the neural tube during development. As the neural tube begins to develop, the notochord begins to secrete a factor known as Sonic hedgehog or SHH. As a result, the floor plate then also begins to secrete SHH, and this will induce the basal plate to develop motor neurons.
Meanwhile, the overlying ectoderm secretes bone morphogenetic protein (BMP). This induces the roof plate to begin to secrete BMP, which will induce the alar plate to develop sensory neurons. The alar plate and the basal plate are separated by the sulcus limitans.
Additionally, the floor plate also secretes netrins. The netrins act as chemoattractants to decussation of pain and temperature sensory neurons in the alar plate across the anterior white commissure, where they then ascend towards the thalamus.
Lastly, it is important to note that the past studies of Viktor Hamburger and Rita Levi-Montalcini in the chick embryo have been further proven by more recent studies which demonstrated that the elimination of neuronal cells by programmed cell death (PCD) is necessary for the correct assembly of the nervous system.
Overall, spontaneous embryonic activity has been shown to play a role in neuron and muscle development but is probably not involved in the initial formation of connections between spinal neurons.


Opsin

Opsins are a group of proteins made light-sensitive via the chromophore retinal (or a variant) found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical signal, the first step in the visual transduction cascade. Another opsin found in the mammalian retina, melanopsin, is involved in circadian rhythms and pupillary reflex but not in vision.
Opsin classification.
Opsins can be classified several ways, including function (vision, phototaxis, photoperiodism, etc.), type of chromophore (retinal, flavine, bilin), molecular structure (tertiary, quaternary), signal output (phosphorylation, reduction, oxidation), etc.
There are two groups of protein termed opsins. Type I opsins are employed by prokaryotes and by some algae (as a component of channelrhodopsins) and fungi, whereas animals use type II opsins. No opsins have been found outside these groups (for instance in plants, or placozoans).
At one time it was thought that type I and type II were related because of structural and functional similarities. With the advent of genetic sequencing it became apparent that sequence identity was no greater than could be accounted for by random chance. However, in recent years new methods have been developed specific to "deep phylogeny". As a result, several studies have found evidence of a possible phylogenetic relationship between the two. However, this does not necessarily mean that the last common ancestor of type I and II opsins was itself an opsin, a light sensitive receptor: all animal opsins arose (by gene duplication and divergence) late in the history of the large G-protein coupled receptor (GPCR) gene family, which itself arose after the divergence of plants, fungi, choanflagellates and sponges from the earliest animals. The retinal chromophore is found solely in the opsin branch of this large gene family, meaning its occurrence elsewhere represents convergent evolution, not homology. Microbial rhodopsins are, by sequence, very different from any of the GPCR families. According to one hypothesis, both type-I and type-II opsins belong to the "transporter-opsin-G protein-coupled receptor (TOG) superfamily", a proposed clade that includes G protein-coupled receptor (GPCR), Ion-translocating microbial rhodopsin (MR), and seven others.
Type I opsins.
Type I opsins (also known as microbial opsins) are seven-transmembrane-domain proteins. Most of them are ion channels or pumps instead of proper receptors and do not bind to a G protein. Type I opsins are found in all three domains of life: Archaea, Bacteria, and Eukaryota. In Eukaryota, type I opsins are found mainly in unicellular organisms such as green algae, and in fungi. In most complex multicellular eukaryotes, type I opsins have been replaced with other light-sensitive molecules such as cryptochrome and phytochrome in plants, and type II opsins in Metazoa (animals).
Microbial opsins are often known by the rhodopsin form of the molecule, i.e., rhodopsin (in the broad sense) = opsin + chromophore. Among the many kinds of microbial opsins are the proton pumps bacteriorhodopsin (BR) and xanthorhodopsin (xR), the chloride pump halorhodopsin (HR)
the photosensors sensory rhodopsin I (SRI) and sensory rhodopsin II (SRII), as well as proteorhodopsin (PR), Neurospora opsin I (NOPI), Chlamydomonas sensory rhodopsins A (CSRA), Chlamydomonas sensory rhodopsins B (CSRB), channelrhodopsin (ChR), and archaerhodopsin (Arch).
Several type I opsins, such as proteo- and bacteriorhodopsin, are used by various bacterial groups to harvest energy from light to carry out metabolic processes using a non-chlorophyll-based pathway. Beside that, halorhodopsins of Halobacteria and channelrhodopsins of some algae, e.g. Volvox, serve them as light-gated ion channels, amongst others also for phototactic purposes. Sensory rhodopsins exist in Halobacteria that induce a phototactic response by interacting with transducer membrane-embedded proteins that have no relation to G proteins.
Type I opsins (like channelrhodopsin, halorhodopsin, and archaerhodopsin) are used in optogenetics to switch on or off neuronal activity. Type I opsins are preferred if the neuronal activity should be modulated at higher frequency, because they respond faster than type II opsins. This is because type I opsins are ion channels or proton/ion pumps and thus are activated by light directly, while type II opsins activate G-proteins, which then activate effector enzymes that produce metabolites to open ion channels.
Type II opsins.
Type II opsins (or animal opsins) are members of the seven-transmembrane-domain proteins (35–55 kDa) of the G protein-coupled receptor (GPCR) superfamily.
Type II opsins fall phylogenetically into four groups: C-opsins (Ciliary), Cnidops (cnidarian opsins), R-opsins (rhabdomeric), and Go/RGR opsins (also known as RGR/Go or Group 4 opsins). The Go/RGR opsins are divided into four sub-clades: Go-opsins, RGR, Peropsins, and Neuropsins. C-opsins, R-opsins, and the Go/RGR opsins are found only in Bilateria.
Type II visual opsins are traditionally classified as either ciliary or rhabdomeric. Ciliary opsins, found in vertebrates and cnidarians, attach to ciliary structures such as rods and cones. Rhabdomeric opsins are attached to light-gathering organelles called rhabdomeres. This classification cuts across phylogenetic categories (clades) so that both the terms "ciliary" and "rhabdomeric" can be ambiguous. Here, "C-opsins (ciliary)" refers to a clade found exclusively in Bilateria and excludes cnidarian ciliary opsins such as those found in the box jellyfish. Similarly, "R-opsin (rhabdomeric)" includes melanopsin even though it does not occur on rhabdomeres in vertebrates.
C-opsins (ciliary).
Ciliary opsins (or c-opsins) are expressed in ciliary photoreceptor cells, and include the vertebrate visual opsins and encephalopsins. They convert light signals to nerve impulses via cyclic nucleotide gated ion channels, which work by increasing the charge differential across the cell membrane (i.e. hyperpolarization.)
Vertebrate visual opsins.
Vertebrate visual opsins are a subset of C-opsins (ciliary). They are expressed in the vertebrate retina and mediate vision. They can be further subdivided into rod opsins and four types of cone opsin. Rod opsins (rhodopsins, usually denoted Rh), are used in dim-light vision, are thermally stable, and are found in the rod photoreceptor cells. Cone opsins, employed in color vision, are less-stable opsins located in the cone photoreceptor cells. Cone opsins are further subdivided according to their absorption maxima ("λ"max), the wavelength at which the highest light absorption is observed. Evolutionary relationships, deduced using the amino acid sequence of the opsins, are also frequently used to categorize cone opsins into their respective group. Both methods predict four general cone opsin groups in addition to rhodopsin.
Vertebrates typically have four cone opsins (LWS, SWS1, SWS2, and Rh2) inherited from the first vertebrate (and thus predating the first vertebrate), as well as the rod opsin, rhodopsin (Rh1), which emerged after the first vertebrate but before the first Gnathostome (jawed vertebrate). These five opsins emerged through a series of gene duplications beginning with LWS and ending with Rh1. Each one has since evolved into numerous variants and thus constitutes an opsin family or subtype.
Humans have the following set of photoreceptor proteins responsible for vision:
Pinopsins.
The first Pineal Opsin (Pinopsin) was found in the chicken pineal gland. It is a blue sensitive opsin ("λ"max = 470 nm).
wide range of expression in the brain, most notably in the pineal region
Vertebrate Ancient (VA) opsin.
Vertebrate Ancient (VA) opsin has three isoforms VA short (VAS), VA medium (VAM), and VA long (VAL). It is expressed in the inner retina, within the horizontal and amacrine cells, as well as the pineal organ and habenular region of the brain. It is sensitive to approximately 500 nm [14], found in most vertebrate classes, but not in mammals.
Parapinopsins.
The first parapinopsin (PP) opsin was found in the parapineal organ of the catfish. The parapinopsin of lamprey is a UV-sensitive opsin ("λ"max = 370 nm). The teleosts have two groups of parapinopsins, one is sensitive to UV ("λ"max = 360-370 nm), the other is sensitive to blue ("λ"max = 460-480 nm) light.
Parietopsins.
The first parietopsin was found in the photoreceptor cells of the lizard parietal eye. The lizard parietopsin is green-sensitive ("λ"max = 522 nm), and despite it is a c-opsin, like the vertebrate visual opsins, it does not induce hyperpolarization via a Gt-protein, but induces depolarization via a Go-protein.
OPN3 (Encephalopsin or Panopsin).
Panopsins are found in many tissues (skin, brain, testes, heart, liver, kidney, skeletal muscle, lung, pancreas and retina). They were originally found in the human and mouse brain and thus called encephalopsin.
The first invertebrate panopsin was found in the ciliary photoreceptor cells of the annelid "Platynereis dumerilii" and is called c(iliary)-opsin. This c-opsin is UV-sensitive ("λ"max = 383 nm) and can be tuned by 125 nm at a single amino-acid (range "λ"max = 377 - 502 nm). Thus, not unsurprisingly, a second but cyan sensitive c-opsin ("λ"max = 490 nm) exists in "Platynereis dumerilii". The first c-opsin mediates in the larva UV induced gravitaxis. The gravitaxis forms with phototaxis a ratio-chromatic depth-gauge. In different depths, the light in water is composed of different wavelengths: First the red (> 600 nm) and the UV and violet (< 420 nm) wavelengths disappear. The higher the depth the narrower the spectrum so that only cyan light (480 nm) is left. Thus, the larvae can determine their depth by color. The color unlike brightness stays almost constant independent of time of day or the weather, for instance if it is cloudy.
Panopsins are also expressed in the brains of some insects. The panopsins of mosquito and pufferfish absorb maximally at 500 nm and 460 nm, respectively. Both activate in vitro Gi and Go proteins.
The panopsins of teleost fish are called: Teleost multiple tissue (TMT) opsins.
Teleost Multiple Tissue (TMT) Opsin.
Teleost fish opsins are expressed in many tissues and therefore called Teleost Multiple Tissue (TMT) opsins. TMT opsins form three groups which are most closely related to a fourth groups the panopsins. In fact, TMT opsins in teleost fish are orthologous to the panopsins in the other vertebrates. They also have the same introns and the same place, which confirms that they belong together.
Cnidarian opsins.
Cnidaria, which include jellyfish, corals, and sea anemones, are the most basal animals to possess complex eyes. Jellyfish opsins in the rhopalia couple to Gs-proteins raising the intracellular cAMP level. Coral opsins can couple to Gq-proteins and Gc-proteins. Gc-proteins are a subtype of G-proteins specific to cnidarians. The cnidarian opsins have been identified as one group and so called cnidops, however at least some of them belong to the c-opsins, r-opsins, and Go/RGR-opsins found in bilaterians.
r-opsins (rhabdomeric) / Gq-coupled.
Rhabdomeric opsins (or r-opsins) are also known as Gq-opsins, because they couple to a Gq-protein. R-opsins are used by molluscs and arthropods. Arthropods appear to attain colour vision in a similar fashion to the vertebrates, by using three (or more) distinct groups of opsins, distinct both in terms of phylogeny and spectral sensitivity. The r-opsin melanopsin is also expressed in vertebrates, where it regulates circadian rhythms and mediates the pupillary reflex.
Unlike c-opsins, r-opsins are associated with canonical transient receptor potential ion channels; these lead to the electric potential difference across a cell membrane being eradicated (i.e. depolarization).
The identification of the crystal structure of squid rhodopsin is likely to further our understanding of its function in this group.
Arthropods use different opsins in their different eye types, but at least in "Limulus" the opsins expressed in the lateral and the compound eyes are 99% identical and presumably diverged recently.
Melanopsin OPN4.
Involved in circadian rhythms, pupillary reflex, and color correction in high-brightness situations. Phylogenetically a member of the R-opsin (rhabdomeric) group, functionally and structurally an r-opsin, but does not occur in rhabdomeres.
Go/RGR (Group 4) opsins.
Go/RGR opsins include Go-opsins, RGR-opsins, neuropsins, and peropsins.
Go-opsins.
Go-opsins are absent from higher vertebrates and ecdysozoans. They are found in the ciliary photoreceptor cells of the scallop eye and the basal chordate amphioxus. In "Platynereis dumerilii" however, a Go-opsin is expressed in the rhabdomeric photoreceptor cells of the eyes.
RGR opsins.
RGR opsins, also known as Retinal G protein coupled receptors are expressed in the retinal pigment epithelium (RPE) and Müller cells. They preferentially bind all-trans-retinal in the dark instead of 11-cis-retinal. RGR opsins were thought to be photomerases but instead, they regulate retinoid traffic and production. In particular, they speed up light-independently the production of 11-cis-retinol (a precursor of 11-cis-retinal) from all-trans-retinyl-esters. However, the all-trans-retinyl-esters are made available light-dependently by RGR-opsins. Whether RGR-opsins regulate this via a G-protein or another signaling mechanism is unknown. The cattle RGR opsin absorbs maximally at different wavelengths depending on the pH-value. At high pH it absorbs maximally blue (469 nm) light and at low pH it absorbs maximally UV (370 nm) light.
Peropsin.
Peropsin, a visual pigment-like receptor, is a protein that in humans is encoded by the "RRH" gene.
Neuropsins.
Neuropsins are sensitive to UVA, typically at 380 nm. They are found in the brain, testes, skin, and retina of humans and rodents, as well as in the brain and retina of birds. In birds and rodents they mediate ultraviolet vision. They couple to Gi-proteins. In humans, Neuropsin is encoded by the OPN5 gene. In the human retina, its function is unknown. In the mouse, it photo-entrains the retina and cornea at least ex vivo.
Unclassified.
Extraretinal (or extra-ocular) Rhodopsin-Like Opsins (Exo-Rh).
These pineal opsins, found in the Actinopterygii (ray-finned fish) apparently arose as a result of gene duplication from Rh1 (rhodopsin). These opsins appear to serve functions similar to those of pinopsin found in birds and reptiles.
Structure and function.
Opsin proteins covalently bind to a vitamin A-based retinaldehyde chromophore through a Schiff base linkage to a lysine residue in the seventh transmembrane alpha helix. In vertebrates, the chromophore is either 11-"cis"-retinal (A1) or 11-"cis"-3,4-didehydroretinal (A2) and is found in the retinal binding pocket of the opsin. The absorption of a photon of light results in the photoisomerization of the chromophore from the 11-"cis" to an all-"trans" conformation. The photoisomerization induces a conformational change in the opsin protein, causing the activation of the phototransduction cascade. The opsin remains insensitive to light in the "trans" form. It is regenerated by the replacement of the all-"trans" retinal by a newly synthesized 11-"cis"-retinal provided from the retinal epithelial cells. Opsins are functional while bound to either chromophore, with A2-bound opsin "λ"max being at a longer wavelength than A1-bound opsin.
Opsins contain seven transmembrane α-helical domains connected by three extra-cellular and three cytoplasmic loops. Many amino acid residues, termed "functionally conserved residues", are highly conserved between all opsin groups, indicative of important functional roles. All residue positions discussed henceforth are relative to the 348 amino acid bovine rhodopsin crystallized by Palczewski "et al." Lys296 is conserved in all known opsins and serves as the site for the Schiff base linkage with the chromophore. Cys138 and Cys110 form a highly conserved disulfide bridge. Glu113 serves as the counterion, stabilizing the protonation of the Schiff linkage between Lys296 and the chromophore. The Glu134-Arg135-Tyr136 is another highly conserved motif, involved in the propagation of the transduction signal once a photon has been absorbed.
Certain amino acid residues, termed "spectral tuning sites", have a strong effect on "λ"max values. Using site-directed mutagenesis, it is possible to selectively mutate these residues and investigate the resulting changes in light absorption properties of the opsin. It is important to differentiate "spectral tuning sites", residues that affect the wavelength at which the opsin absorbs light, from "functionally conserved sites", residues important for the proper functioning of the opsin. They are not mutually exclusive, but, for practical reasons, it is easier to investigate spectral tuning sites that do not affect opsin functionality. For a comprehensive review of spectral tuning sites see Yokoyama and Deeb. The impact of spectral tuning sites on "λ"max differs between different opsin groups and between opsin groups of different species.
Opsins in the human eye, brain, and skin.
RPE, retinal pigment epithelium; ipRGC, intrinsically photosensitive retinal ganglion cells; OPL, outer plexiform layer; IPL, inner plexiform layer; GCL, ganglion cell layer


Olfactory system

The olfactory system, or sense of smell, is the sensory system used for smelling (olfaction). Olfaction is one of the special senses, that have directly associated specific organs. Most mammals and reptiles have a main olfactory system and an accessory olfactory system. The main olfactory system detects airborne substances, while the accessory system senses fluid-phase stimuli.
The senses of smell and taste (gustatory system) are often referred to together as the chemosensory system, because they both give the brain information about the chemical composition of objects through a process called transduction.
Structure.
Peripheral.
The peripheral olfactory system consists mainly of the nostrils, ethmoid bone, nasal cavity, and the olfactory epithelium (layers of thin tissue covered in mucus that line the nasal cavity). The primary components of the layers of epithelial tissue are the mucous membranes, olfactory glands, olfactory neurons, and nerve fibers of the olfactory nerves.
Odor molecules can enter the peripheral pathway and reach the nasal cavity either through the nostrils when inhaling (olfaction) or through the throat when the tongue pushes air to the back of the nasal cavity while chewing or swallowing (retro-nasal olfaction). Inside the nasal cavity, mucus lining the walls of the cavity dissolves odor molecules. Mucus also covers the olfactory epithelium, which contains mucous membranes that produce and store mucus and olfactory glands that secrete metabolic enzymes found in the mucus.
Transduction.
Olfactory sensory neurons in the epithelium detect odor molecules dissolved in the mucus and transmit information about the odor to the brain in a process called sensory transduction. Olfactory neurons have cilia (tiny hairs) containing olfactory receptors that bind to odor molecules, causing an electrical response that spreads through the sensory neuron to the olfactory nerve fibers at the back of the nasal cavity.
Olfactory nerves and fibers transmit information about odors from the peripheral olfactory system to the central olfactory system of the brain, which is separated from the epithelium by the cribriform plate of the ethmoid bone. Olfactory nerve fibers, which originate in the epithelium, pass through the cribriform plate, connecting the epithelium to the brain's limbic system at the olfactory bulbs.
Central.
The main olfactory bulb transmits pulses to both mitral and tufted cells, which help determine odor concentration based on the time certain neuron clusters fire (called 'timing code'). These cells also note differences between highly similar odors and use that data to aid in later recognition. The cells are different with mitral having low firing-rates and being easily inhibited by neighboring cells, while tufted have high rates of firing and are more difficult to inhibit.
The uncus houses the olfactory cortex which includes the piriform cortex (posterior orbitofrontal cortex), amygdala, olfactory tubercle, and parahippocampal gyrus.
The olfactory tubercle connects to numerous areas of the amygdala, thalamus, hypothalamus, hippocampus, brain stem, retina, auditory cortex, and olfactory system. *In total it has 27 inputs and 20 outputs. An oversimplification of its role is to state that it: checks to ensure odor signals arose from actual odors rather than villi irritation, regulates motor behavior (primarily social and stereotypical) brought on by odors, integrates auditory and olfactory sensory info to complete the aforementioned tasks, and plays a role in transmitting positive signals to reward sensors (and is thus involved in addiction).
The amygdala (in olfaction) processes pheromone, allomone, and kairomone (same-species, cross-species, and cross-species where the emitter is harmed and the sensor is benefited, respectively) signals. Due to cerebrum evolution this processing is secondary and therefore is largely unnoticed in human interactions. Allomones include flower scents, natural herbicides, and natural toxic plant chemicals. The info for these processes comes from the vomeronasal organ indirectly via the olfactory bulb. The main olfactory bulb's pulses in the amygdala are used to pair odors to names and recognize odor to odor differences.
Stria terminalis, specifically bed nuclei (BNST), act as the information pathway between the amygdala and hypothalamus, as well as the hypothalamus and pituitary gland. BNST abnormalities often lead to sexual confusion and immaturity. BNST also connects to the septal area, rewarding sexual behavior.
Mitral pulses to the hypothalamus promote/discourage feeding, whereas accessory olfactory bulb pulses regulate reproductive and odor-related-reflex processes.
The hippocampus (although minimally connected to the main olfactory bulb) receives almost all of its olfactory information via the amygdala (either directly or via the BNST). The hippocampus forms new and reinforces existing memories.
Similarly, the parahippocampus encodes, recognizes and contextualizes scenes. The parahippocampal gyrus houses the topographical map for olfaction.
The orbitofrontal cortex (OFC) is heavily correlated with the cingulate gyrus and septal area to act out positive/negative reinforcement. The OFC is the expectation of reward/punishment in response to stimuli. The OFC represents the emotion and reward in decision making.
The anterior olfactory nucleus distributes reciprocal signals between the olfactory bulb and piriform cortex. The anterior olfactory nucleus is the memory hub for smell.
Clinical significance.
Loss of smell is known as anosmia. Anosmia can occur on both sides or a single side.
Olfactory problems can be divided into different types based on their malfunction. The olfactory dysfunction can be total (anosmia), incomplete (partial anosmia, hyposmia, or microsmia), distorted (dysosmia), or can be characterized by spontaneous sensations like phantosmia. An inability to recognize odors despite a normally functioning olfactory system is termed olfactory agnosia. Hyperosmia is a rare condition typified by an abnormally heightened sense of smell. Like vision and hearing, the olfactory problems can be bilateral or unilateral meaning if a person has anosmia on the right side of the nose but not the left, it is a unilateral right anosmia. On the other hand, if it is on both sides of the nose it is called bilateral anosmia or total anosmia.
Destruction to olfactory bulb, tract, and primary cortex (brodmann area 34) results in anosmia on the same side as the destruction. Also, irritative lesion of the uncus results in olfactory hallucinations.
Damage to the olfactory system can occur by traumatic brain injury, cancer, infection, inhalation of toxic fumes, or neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. These conditions can cause anosmia. In contrast, recent finding suggested the molecular aspects of olfactory dysfunction can be recognized as a hallmark of amyloidogenesis-related diseases and there may even be a causal link through the disruption of multivalent metal ion transport and storage. Doctors can detect damage to the olfactory system by presenting the patient with odors via a scratch and sniff card or by having the patient close their eyes and try to identify commonly available odors like coffee or peppermint candy.
Doctors must exclude other diseases that inhibit or eliminate 'the sense of smell' such as chronic colds or sinusitus before making the diagnosis that there is permanent damage to the olfactory system.
Prevalence of olfactory dysfunction in the general US population was assessed by questionnaire and examination in a national health survey in 2012-2014. Among over a thousand persons aged 40 years and older, 12.0% reported a problem with smell in the past 12 months and 12.4% had olfactory dysfunction on examination. Prevalence rose from 4.2% at age 40-49 to 39.4% at 80 years and older and was higher in men than women, in blacks and Mexican Americans than in whites and in less than more educated. Of concern for safety, 20% of persons aged 70 and older were unable to identify smoke and 31%, natural gas.
Causes of olfactory dysfunction.
The common causes of olfactory dysfunction: advanced age, viral infections, exposure to toxic chemicals, head trauma, and neurodegenerative diseases.
Age.
Age is the strongest reason for olfactory decline in healthy adults, having even greater impact than does cigarette smoking. Age-related changes in smell function often go unnoticed and smell ability is rarely tested clinically unlike hearing and vision. 2% of people under 65 years of age have chronic smelling problems. This increases greatly between people of ages 65 and 80 with about half experiencing significant problems smelling. Then for adults over 80, the numbers rise to almost 75%. The basis for age-related changes in smell function include closure of the cribriform plate, and cumulative damage to the olfactory receptors from repeated viral and other insults throughout life.
Viral infections.
The most common cause of permanent hyposmia and anosmia are upper respiratory infections. Such dysfunctions show no change over time and can sometimes reflect damage not only to the olfactory epithelium, but also to the central olfactory structures as a result of viral invasions into the brain. Among these virus-related disorders are the common cold, hepatitis, influenza and influenza-like illness, as well as herpes. Notably, COVID-19 is associated with olfactory disturbance. Most viral infections are unrecognizable because they are so mild or entirely asymptomatic.
Exposure to toxic chemicals.
Chronic exposure to some airborne toxins such as herbicides, pesticides, solvents, and heavy metals (cadmium, chromium, nickel, and manganese), can alter the ability to smell. These agents not only damage the olfactory epithelium, but they are likely to enter the brain via the olfactory mucosa.
Head trauma.
Trauma-related olfactory dysfunction depends on the severity of the trauma and whether strong acceleration/deceleration of the head occurred. Occipital and side impact causes more damage to the olfactory system than frontal impact. However, recent evidence from individuals with traumatic brain injury suggests that smell loss can occur with changes in brain function outside of olfactory cortex.
Neurodegenerative diseases.
Neurologists have observed that olfactory dysfunction is a cardinal feature of several neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Most of these patients are unaware of an olfactory deficit until after testing where 85% to 90% of early-stage patients showed decrease activity in central odor processing structures.
Other neurodegenerative diseases that affect olfactory dysfunction include Huntington's disease, multi-infarct dementia, amyotrophic lateral sclerosis, and schizophrenia. These diseases have more moderate effects on the olfactory system than Alzheimer's or Parkinson's diseases. Furthermore, progressive supranuclear palsy and parkinsonism are associated with only minor olfactory problems. These findings have led to the suggestion that olfactory testing may help in the diagnosis of several different neurodegenerative diseases.
Neurodegenerative diseases with well-established genetic determinants are also associated with olfactory dysfunction. Such dysfunction, for example, is found in patients with familial Parkinson's disease and those with Down syndrome. Further studies have concluded that the olfactory loss may be associated with intellectual disability, rather than any Alzheimer's disease-like pathology.
Huntington's disease is also associated with problems in odor identification, detection, discrimination, and memory. The problem is prevalent once the phenotypic elements of the disorder appear, although it is unknown how far in advance the olfactory loss precedes the phenotypic expression.
History.
Linda B. Buck and Richard Axel won the 2004 Nobel Prize in Physiology or Medicine for their work on the olfactory system.


Mabuhay

Mabuhay is a Filipino greeting, usually expressed as "Mabuhay!", in the imperative form of "life", thus, "Live!", from the root word "buhay" (life). Its real intentional meaning is “Long live!”
Meaning.
The phrase carries various meanings including "long live", "may you live", "cheers", "welcome", and "hurrah". It is thus analogous to Aloha, Talofa and Kia Ora in fellow Austronesian languages, Hawaiian, Samoan and Māori; the Romance language expression “Vive, Viva”, the Hindustani suffix "Zindabad", and the Japanese exclamation "Banzai".
Usage.
The expression is mostly used for toasts during gatherings and parties, and is used as a cry of adulation towards individuals or concepts at rallies and political conferences. A more modern appropriation of the greeting is its use in the local hospitality industry to welcome guests—a practice rooted in a 1993 campaign launched by restaurateur Rod Ongpauco to more uniquely welcome foreign visitors to the Philippines.
"Mabuhay" is also the name of the inflight magazine published by Philippine Airlines.
Cognates in other languages.
A number of other Philippine languages have terms that are cognate with the term. The Bisayan languages, for example, use the term "Mabuhi" in a manner similar to "Mabuhay".
Viva.
Alternatively, the Spanish equivalent "Viva" is used in almost exclusively religious contexts, specifically in shouts of praise directed at a patron saint or to God during fiestas and assemblies (e.g., "¡Viva Señor Santo Niño!")


Loop interchange

In compiler theory, loop interchange is the process of exchanging the order of two iteration variables used by a nested loop. The variable used in the inner loop switches to the outer loop, and vice versa. It is often done to ensure that the elements of a multi-dimensional array are accessed in the order in which they are present in memory, improving locality of reference.
For example, in the code fragment:
 for i from 0 to 10
 for j from 0 to 20
 a[i,j] = i + j
loop interchange would result in:
 for j from 0 to 20
 for i from 0 to 10
 a[i,j] = i + j
On occasion, such a transformation may create opportunities to further optimize, such as automatic vectorization of the array assignments.
The utility of loop interchange.
The major purpose of loop interchange is to take advantage of the CPU cache when accessing array elements. When a processor accesses an array element for the first time, it will retrieve an entire block of data from memory to cache. That block is likely to have many more consecutive elements after the first one, so on the next array element access, it will be brought directly from cache (which is faster than getting it from slow main memory). Cache misses occur if the contiguously accessed array elements within the loop come from a different cache block, and loop interchange can help prevent this. The effectiveness of loop interchange depends on and must be considered in light of the cache model used by the underlying hardware and the array model used by the compiler.
In C programming language, array elements in the same row are stored consecutively in memory (a[1,1], a[1,2], a[1,3]) ‒ in row-major order. On the other hand, FORTRAN programs store array elements from the same column together (a[1,1], a[2,1], a[3,1]), using column-major. Thus the order of two iteration variables in the first example is suitable for a C program while the second example is better for FORTRAN. Optimizing compilers can detect the improper ordering by programmers and interchange the order to achieve better cache performance.
Caveat.
Like any compiler optimization, loop interchange may lead to worse performance because cache performance is only part of the story. Take the following example:
 do i = 1, 10000
 do j = 1, 1000
 a[i] = a[i] + b[j,i] * c[i]
 end do
 end do
Loop interchange on this example can improve the cache performance of accessing b(j,i), but it will ruin the reuse of a(i) and c(i) in the inner loop, as it introduces two extra loads (for a(i) and for c(i)) and one extra store (for a(i)) during each iteration. As a result, the overall performance may be degraded after loop interchange.
Safety.
It is not always safe to exchange the iteration variables due to dependencies between statements for the order in which they must execute. To determine whether a compiler can safely interchange loops, dependence analysis is required.


Imre Bajor

Imre Bajor (9 March 1957 – 6 August 2014) was a Hungarian actor and comedian.


Qalbi

Qalbi, قلبي, also transcribed albee and galbi, is the Arabic word for "my heart." It is used as a term of endearment.
"Qalbi" is also the Maltese word for "my heart". Maltese is a Semitic language and has many words similar to those in the Arabic language, even in pronunciation.


Intercostal nerves

The intercostal nerves are part of the somatic nervous system, and arise from the anterior rami of the thoracic spinal nerves from T1 to T11. The intercostal nerves are distributed chiefly to the thoracic pleura and abdominal peritoneum, and differ from the anterior rami of the other spinal nerves in that each pursues an independent course without plexus formation.
The first two nerves supply fibers to the upper limb and thorax; the next four distribute to the walls of the thorax; the lower five supply the walls of the thorax and abdomen. The 7th intercostal nerve end at the xyphoid process of the sternum. The 10th intercostal nerve terminates at the navel. The 12th (subcostal) thoracic is distributed to the walls of the abdomen and groin. Each of these fibers contains around 1300 axons.
Unlike the nerves from the autonomic nervous system that innervate the visceral pleura of the thoracic cavity, the intercostal nerves arise from the somatic nervous system. This enables them to control the contraction of muscles, as well as provide specific sensory information regarding the skin and parietal pleura. This explains why damage to the internal wall of the thoracic cavity can be felt as a sharp pain localized in the injured region. Damage to the visceral pleura is experienced as an un-localized ache.
The 1st thoracic nerve.
The anterior division of the first thoracic nerve divides into two branches. The larger branch leaves the thorax in front of the neck of the first rib, and enters the brachial plexus. The smaller branch, the first intercostal nerve, runs along the first intercostal space, and ends on the front of the chest as the first anterior cutaneous branch of the thorax. Occasionally, this anterior cutaneous branch is missing.
The first intercostal nerve rarely gives off a lateral cutaneous branch; but sometimes sends a small branch to communicate with the intercostobrachial.
From the second thoracic nerve it frequently receives a connecting twig, which ascends over the neck of the second rib. This nerve was first described by Kuntz in 1927. There is considerable anatomic variation, but Kuntz nerve may be present in 40-80% of the population.
The upper thoracic nerves: 2nd–6th.
The anterior divisions of the second, third, fourth, fifth, and sixth thoracic nerves, and the small branch from the first thoracic, are confined to the walls of the thorax, and are named thoracic intercostal nerves.
They pass forward in the intercostal spaces below the intercostal vessels. At the back of the chest they lie between the pleura and the posterior intercostal membranes, but soon they run between the internal intercostals and the innermost intercostals then anteriorly they lie between the pleura and the internal intercostals.
Near the sternum, they cross in front of the internal mammary artery and transversus thoracis muscle, pierce the intercostales interni, the anterior intercostal membranes, and pectoralis major, and supply the integument of the front of the thorax and over the mamma, forming the anterior cutaneous branches of the thorax; the branch from the second nerve unites with the anterior supraclavicular nerves of the cervical plexus.
The fourth intercostal nerve is innervated by cutaneous slowly-adapting and rapidly-adapting mechanoreceptors, especially by ones densely-packed under the areola; innervation subsequently triggers oxytocin release, which, when in the peripheral bloodstream, causes myoepithelial cell contraction and lactation: this is an example of a non-nerve-innervation muscular reflex.
Branches.
Numerous slender muscular filaments supply the Intercostales, the Subcostales, the Levatores costarum, the Serratus posterior superior, and the Transversus thoracis. At the front of the thorax some of these branches cross the costal cartilages from one intercostal space to another.
The lateral cutaneous branch of the second intercostal nerve does not divide, like the others, into an anterior and a posterior branch; it is named the intercostobrachial nerve.
The lower thoracic nerves: 12th.
Lateral cutaneous branch.
The lateral cutaneous branch of the last thoracic nerve is large, and undivided.
It perforates the internal and the external oblique muscles, descends over the iliac crest in front of the lateral cutaneous branch of the iliohypogastric nerve, and is distributed to the skin of the front part of the gluteal muscles, some of its filaments extending as low as the greater trochanter of the femur.


Batch effect

In molecular biology, a batch effect occurs when non-biological factors in an experiment cause changes in the data produced by the experiment. Such effects can lead to inaccurate conclusions when their causes are correlated with one or more outcomes of interest in an experiment. They are common in many types of high-throughput sequencing experiments, including those using microarrays, mass spectrometers, and single-cell RNA-sequencing data. They are most commonly discussed in the context of genomics and high-throughput sequencing research, but they exist in other fields of science as well.
Definitions.
Multiple definitions of the term "batch effect" have been proposed in the literature. Lazar et al. (2013) noted, "Providing a complete and unambiguous definition of the so-called batch effect is a challenging task, especially because its origins and the way it manifests in the data are not completely known or not recorded." Focusing on microarray experiments, they propose a new definition based on several previous ones: "[T]he batch effect represents the systematic technical differences when samples are processed and measured in different batches and which are unrelated to any biological variation recorded during the MAGE [microarray gene expression] experiment."
Causes.
Many potentially variable factors have been identified as potential causes of batch effects, including the following:
Correction.
Various statistical techniques have been developed to attempt to correct for batch effects in high-throughput experiments. These techniques are intended for use during the stages of experimental design and data analysis. They have historically mostly focused on genomics experiments, and have only recently begun to expand into other scientific fields such as proteomics. One problem associated with such techniques is that they may unintentionally remove actual biological variation. Some techniques that have been used to detect and/or correct for batch effects include the following:


Outline of the human brain

The following outline is provided as an overview of and topical guide to the human brain:
Human brain – central organ of the nervous system located in the head of a human being, protected by the skull. It has the same general structure as the brains of other mammals, but with a more developed cerebral cortex than any other, leading to the evolutionary success of widespread dominance of the human species across the planet.
While the emphasis below is on physical brain structure, functional aspects are also included. Mind concepts (as in mind vs. body), and cognitive and behavioral aspects, are introduced where they have at least a fairly direct connection to physical aspects of the brain, neurons, spinal cord, nerve networks, neurotransmitters, etc.
Structure of the human brain.
This major section covers the physical structure of the brain.
Brain development.
This development section covers "over time" changes in brain structure. It includes normal development of the human brain from infant to adult, brain genetics (over many generations) and the evolution and adaptation of the brain over millions of years.
Typical brain function.
This section covers typical brain function as opposed to atypical function discussed below.
Atypical brain function.
This section covers the major known deviations from typical brain functioning with an emphasis on the resulting magnitude of overall human suffering.
Physical interventions.
This section covers man's attempts to physically alter the brain state to relieve suffering, address atypical functioning or improve performance.


Lea De Mae

Andrea Absolonová (26 December 1976 – 9 December 2004), better known by the pseudonym Lea De Mae, was a Czech adult model, pornographic actress and a member of the Czech high diving national team. Mae died from brain cancer on 9 December 2004, at the age of 27.
Biography.
Born in Czechoslovakia, De Mae was a member of the Czech high diving national team and injured her spine in an accident when training for the 1996 Summer Olympics in Atlanta, diving from the 10m platform. She recovered from her injury, but did not qualify for the 2000 Sydney Olympics. Her problems persisted, so she retired from professional sports.
De Mae was later persuaded by a photographer to pose nude and eventually to participate in the adult film industry.
De Mae appeared in over 80 adult films. She first appeared on American screens in a series of features for Private Media Group. She eventually returned to Europe, shooting more films but, after a brief period of time, returned to the States.
De Mae was diagnosed with glioblastoma, an aggressive form of brain cancer in July 2004. Fans and fellow porn actors contributed to a medical fund set up for her in Prague, but she died on 9 December 2004 at the age of 27.


Kaliotoxin

Kaliotoxin (KTX) inhibits potassium flux through the Kv1.3 voltage-gated potassium channel and calcium-activated potassium channels by physically blocking the channel-entrance and inducing a conformational change in the K+-selectivity filter of the channel.
Sources.
KTX is a neurotoxin derived from the scorpion Androctonus mauretanicus mauretanicus, which is found in the Middle East and North Africa. (Crest M et al.)
Chemistry.
Kaliotoxin is a 4-kDa polypeptide chain, containing 38 amino acids. The formula is C171H283N55O49S8. The sequence has a large homology with iberiotoxin from "Buthus tumulus", charybdotoxin from "Leiurus quinquestriatus" and noxiustoxin from "Centruroides noxius".
An Important site of the toxin is the K27 side chain (a lysine at place 27 of the protein sequence), which enters the pore and protrudes into the selectivity filter of the channel. (Lange A et al., Korukottu J et al.)
Target.
KTX binds to the Kv1.3 voltage-gated potassium channel and the Calcium-activated potassium channels (BK channels). (Lange A et al., Crest M et al., Zachariae U et al., Aiyar J et al.,)
These channels control several regulating processes, including neurotransmitter release, heart rate, insulin secretion, smooth muscle contraction. (Wickenden A et al.) Kv1.3 channels also play a critical role in regulating the function of effector memory T cells, the subset implicated in many autoimmune disorders, and blockade of Kv1.3 channels by kaliotoxin ameliorates disease in rat models of multiple sclerosis and bone resorption due to periodontitis. (Beeton C et al., Valverde P et al., Cahalan and Chandy)
Mode of action.
The toxin binds to the external vestibule of the channel, and a critical lysine residue (K27), protrudes into the pore and plugs it (Aiyar J et al., 1995, 1996). The positively charged amino-group of the K27 chain fits into the selectivity filter near the G77 chain (Glycine) of the channel, causing a conformational change of the channels´ selectivity filter (Aiyar J et al., 1996). Thereby the hydrophobic groups of the K27 side chain replace water molecules in the entry region of the pore. So the pore is blocked by a direct plug into the pore region of the channel and a conformational change in the selectivity filter is induced. By determining the solution structure of kaliotoxin and related toxins, and by using complementary mutagenesis and electrostatic compliance, it was possible to determine the architecture of the toxin binding site at the outer vestibule of the Kv1.3 channel (Aiyar J et al., 1995, 1996). This vestibule is - 28-32 A wide at its outer margin, - 28-34 A wide at its base, and -4-8 A deep; the pore is 9-14 ~A wide at its external entrance and tapers to a width of 4-5 A at a depth of - 5-7 A from the vestibule (Aiyar J et al., 1995, 1996). These dimensions are remarkably similar to that of the outer vestibule of the KcsA bacterial channel that was determined by X-ray crystallography (Doyle et al., MacKinnon et al., Lange A et al., Catterall WA et al.)


Optics and vision

Vision of humans and other organisms depends on several organs such as the lens of the eye, and any vision correcting devices, which use optics to focus the image.
The eyes of many animals contains a lens that focuses the light of its surroundings onto the retina of the eye. This lens is essential to producing clear images within the eye.
However, some individuals may have problems with focus, such as myopia or presbyopia. In this case, the focus of the eyes can be corrected with an external lens, such as glasses or contact lenses, or through surgery.
Visual perception.
Visual perception is the ability to interpret information and surroundings from visible light reaching the eye. The resulting perception is also known as eyesight, sight or vision. The various physiological components involved in vision are referred to collectively as the visual system, and are the focus of much research in psychology, cognitive science, neuroscience and molecular biology.
Human Visual system.
The visual system in humans allows individuals to assimilate information from the environment. The act of seeing starts when the lens of the eye focuses an image of its surroundings onto a light-sensitive membrane in the back of the eye, called the retina. The retina converts patterns of light into neuronal signals. The lens of the eye focuses light on the photoreceptive cells of the retina, which detect the photons of light and respond by producing neural impulses. These signals are processed in a hierarchical fashion by different parts of the brain, from the retina to the lateral geniculate nucleus, to the primary and secondary visual cortex of the brain. Signals from the retina can also travel directly from the retina to the Superior colliculus.
Human eye.
The human eye is an organ which reacts to light for several purposes.
As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth. The human eye can distinguish about 10 million colors.
The human eye's non-image-forming photosensitive ganglion cells in the retina receive the light signals which affect adjustment of the size of the pupil, regulation and suppression of the hormone melatonin and entrainment of the body clock.
Visual acuity.
Visual acuity is acuteness or clearness of vision, especially form vision, which is dependent on the sharpness of the retinal focus within the eye and the sensitivity of the interpretative faculty of the brain.
Visual acuity is a quantitative measure of the ability to identify black symbols on a white background at a standardized distance as the size of the symbols is varied. It is the most common clinical measurement of visual function. In the term "20/20 vision" the numerator refers to the distance in feet from which a person can reliably distinguish a pair of objects. The denominator is the distance from which an 'average' person would be able to distinguish —the distance at which their separation angle is 1 arc minute. The metric equivalent is 6/6 vision where the distance is 6 meters. The 20/"x" number does not directly relate to the eyeglass prescription required to correct vision; rather an eye exam seeks to find the prescription that will provide at least 20/20 vision.
Non-Surgical Visual Correction.
Corrective lens.
A corrective lens is a lens worn in front of the eye, mainly used to treat myopia, hyperopia, astigmatism, and presbyopia. The goal is to bring vision up to 20/20 vision or as close to this as possible. Glasses or "spectacles" are corrective lenses worn on the face a short distance in front of the eye. Contact lenses are worn directly on the surface of the eye. Intraocular lenses are surgically implanted most commonly after cataract removal, but recently for purely refractive purposes. Myopia (short sightedness) requires a divergent lens, whereas hyperopia (far sightedness) requires convergent lens.
Prescription of corrective lenses.
Corrective lenses are typically prescribed by an optometrist. The prescription consists of all the specifications necessary to make the lens. Prescriptions typically include the power specifications of each lens (for each eye). Strengths are generally prescribed in quarter-diopter steps (0.25 D) because most people cannot generally distinguish between smaller increments (ex. eighth-diopter steps / 0.125 D).
Glasses.
Glasses (also called eyeglasses or spectacles) are frames bearing lenses worn in front of the eyes, normally for vision correction, eye protection, or for protection from UV rays.
Modern glasses are typically supported by pads on the bridge of the nose and by temple arms placed over the ears. Historical types include the "pince-nez", monocle, lorgnette, and scissors-glasses.
Eyeglass lenses are commonly made from plastic, including CR-39 and polycarbonate. These materials reduce the danger of breakage and weigh less than glass lenses. Some plastics also have more advantageous optical properties than glass, such as better transmission of visible light and greater absorption of ultraviolet light. Some plastics have a greater index of refraction than most types of glass; this is useful in the making of corrective lenses shaped to correct various vision abnormalities such as myopia, allowing thinner lenses for a given prescription.
Contact lenses.
A contact lens (also known simply as a contact) is a corrective, cosmetic, or therapeutic lens usually placed on the cornea of the eye. Modern soft contact lenses were invented by the Czech chemist Otto Wichterle and his assistant Drahoslav Lím, who also invented the first gel used for their production.
Contact lenses usually serve the same corrective purpose as glasses, but are lightweight and virtually invisible—many commercial lenses are tinted a faint blue to make them more visible when immersed in cleaning and storage solutions. Some cosmetic lenses are deliberately colored to alter the appearance of the eye. Lenses now have a slight bluish tint which is a thin UV coating; this reduces glare and cornea damage much like a pair of sunglasses.
Surgical Vision Correction.
Photorefractive keratectomy.
Photorefractive keratectomy (PRK) and Laser-Assisted Sub-Epithelial Keratectomy (or Laser Epithelial Keratomileusis) (LASEK) are laser eye surgery procedures intended to correct a person's vision, reducing dependency on glasses or contact lenses. The first LASEK procedure was performed at Massachusetts Eye and Ear Infirmary in 1996 by ophthalmologist, refractive surgeon, Dimitri Azar. The procedure was later popularized by Camellin, who coined the term LASEK for laser epithelial keratomileusis.
LASEK and PRK permanently change the shape of the anterior central cornea using an excimer laser to ablate (remove by vaporization) a small amount of tissue from the corneal stroma at the front of the eye, just under the corneal epithelium. The outer layer of the cornea is removed prior to the ablation. A computer system tracks the patient's eye position 60 to 4,000 times per second, depending on the brand of laser used, redirecting laser pulses for precise placement. Most modern lasers will automatically center on the patient's visual axis and will pause if the eye moves out of range and then resume ablating at that point after the patient's eye is re-centered.
Cataract Surgery.
Insertion of an intraocular lens for the treatment of cataracts is the most commonly performed eye surgical procedure. The procedure can be done under local anesthesia with the patient awake throughout the operation. The use of a flexible [intraocular lens] enables the lens to be rolled for insertion into the capsule through a very small incision, thus avoiding the need for stitches, and this procedure usually takes less than 30 minutes in the hands of an experienced ophthalmologist. After surgery, patients should avoid strenuous exercise or anything else that significantly increases blood pressure. They should also visit their ophthalmologists regularly for several months so as to monitor the implants.
Most intraocular lenses fitted today are fixed monofocal lenses matched to distance vision. However, other types are available, such as multifocal IOLs which provide the patient with multiple-focused vision at far and reading distance, and adaptive IOLs which provide the patient with limited visual accommodation.


Manidipine

Manidipine is a calcium channel blocker (dihydropyridine type) that is used clinically as an antihypertensive.
It was patented in 1982 and approved for medical use in 1990.


Developmental Neurobiology

Developmental Neurobiology is a monthly peer-reviewed scientific journal covering all aspects of neural development. It was established in 1969 as Journal of Neurobiology, covering all of neuroscience, but when the scope become more specialized, it obtained its current name in 2007. The journal is published by Wiley-Blackwell. The editor-in-chief is Bin Chen (University of California, Santa Cruz) and the associate editors are Song-Hai Shi (Tsinghua University, Beijing, China) and Andreas Prokop (University of Manchester).
Abstracting and indexing.
The journals is abstracted and indexed in:
According to the "Journal Citation Reports", the journal has a 2019 impact factor of 3.935.


Greater occipital nerve

The greater occipital nerve is a spinal nerve, specifically the medial branch of the dorsal primary ramus of cervical spinal nerve 2. This nerve arises from between the first and second cervical vertebrae, along with the lesser occipital nerve. It ascends after emerging from below the suboccipital triangle beneath the obliquus capitis inferior muscle. It then passes through the semispinalis muscle before ascending to innervate the skin along the posterior part of the scalp to the vertex. It innervates the scalp at the top of the head, over the ear and over the parotid glands.
Clinical relevance.
Disorder of this nerve is one of the causes of cervicogenic headaches, referred to as occipital neuralgias. A common site, and usually misdiagnosed area of entrapment for the greater occipital nerve is at the obliquus capitis inferior muscle.
Occipital pain management.
Most people with tension headaches experience increasing intensity with time, and report pain originating in the back of the head (occipital) moving to the front of the head (supraorbital). Neurostimulation is sometimes used to treat tension headaches that originate from the occipital nerve.


Histamine H4 receptor

The histamine H4 receptor, like the other three histamine receptors, is a member of the G protein-coupled receptor superfamily that in humans is encoded by the "HRH4" gene.
Discovery.
Unlike the histamine receptors discovered earlier, H4 was found in 2000 through a search of the human genomic DNA data base.
Tissue distribution.
H4 is highly expressed in bone marrow and white blood cells and regulates neutrophil release from bone marrow and subsequent infiltration in the zymosan-induced pleurisy mouse model. It was also found that H4R exhibits a uniform expression pattern in the human oral epithelium.
Function.
The Histamine H4 receptor has been shown to be involved in mediating eosinophil shape change and mast cell chemotaxis. This occurs via the βγ subunit acting at phospholipase C to cause actin polymerisation and eventually chemotaxis.
Structure.
The 3D structure of the H4 receptor has not been solved yet due to the difficulties of GPCR crystallization. Some attempts have been made to develop structural models of the H4 receptor for different purposes. The first H4 receptor model was built by homology modelling based on the crystal structure of bovine rhodopsin. This model was used for the interpretation of site-directed mutagenesis data, which revealed the crucial importance of Asp94 (3.32) and Glu182 (5.46) residues in ligand binding and receptor activation.
A second rhodopsin based structural model of the H4 receptor was successfully used for the identification of novel H4 ligands.
Recent advancements in GPCR crystallization, in particular the determination of the human histamine H1 receptor in complex with doxepin will likely increase the quality of novel structural H4 receptor models.
Ligands.
Therapeutic potential.
By inhibiting the H4 receptor, asthma and allergy may be treated.
The highly selective histamine H4 antagonist VUF-6002 is orally active and inhibits the activity of both mast cells and eosinophils "in vivo", and has antiinflammatory and antihyperalgesic effects.


Visual routine

A visual routine is a means of extracting information from a visual scene.
In his studies on human visual cognition, Shimon Ullman proposed that the human visual system's task of perceiving shape properties and spatial relations is split into two successive stages: an early "bottom-up" state during which base representations are generated from the visual input, and a later "top-down" stage during which high-level primitives dubbed "visual routines" extract the desired information from the base representations. In humans, the base representations generated during the bottom-up stage correspond to retinotopic maps (more than 15 of which exist in the cortex) for properties like color, edge orientation, speed of motion, and direction of motion. These base representations rely on fixed operations performed uniformly over the entire field of visual input, and do not make use of object-specific knowledge, task-specific knowledge, or other higher-level information.
The visual routines proposed by Ullman are high-level primitives which parse the structure of a scene, extracting spatial information from the base representations. These visual routines are composed of a sequence of elementary visual operators specific to the task at hand. Visual routines differ from the fixed operations of the base representations in that they are not applied uniformly over the entire visual field --- rather, they are only applied to objects or areas specified by the routines.
Ullman lists the following as examples of visual operators: shifting the processing focus, indexing a salient item for further processing, spreading activation over an area delimited by boundaries, tracing boundaries, and marking a location or object for future reference. When combined into visual routines, these elementary operators can be used to perform relatively sophisticated spatial tasks such as counting the number of objects satisfying a certain property, or recognizing a complex shape.
A number of researchers have implemented visual routines for processing camera images, to perform tasks like determining the object a human in the camera image is pointing at. Researchers have also applied the visual routines approach to artificial map representations, for playing real-time 2D video games. In those cases, however, the map of the video game was provided directly, alleviating the need to deal with real-world perceptual tasks like object recognition and occlusion compensation.


Ventral supraoptic decussation

The ventral supraoptic decussation is the crossover (decussation) point for signals from the left and right eye, en route respectively to the right and left sides of the visual cortex.
Occupying the posterior part of the commissure of the optic chiasma is a strand of fibers, the Ventral supraoptic decussation (commissure of Gudden, Gudden's inferior commissure), which is not derived from the optic nerves; it forms a connecting link between the medial geniculate bodies.


Smooth pursuit

In the scientific study of vision, smooth pursuit describes a type of eye movement in which the eyes remain fixated on a moving object. It is one of two ways that visual animals can voluntarily shift gaze, the other being saccadic eye movements. Pursuit differs from the vestibulo-ocular reflex, which only occurs during movements of the head and serves to stabilize gaze on a stationary object. Most people are unable to initiate pursuit without a moving visual signal. The pursuit of targets moving with velocities of greater than 30°/s tends to require catch-up saccades. Smooth pursuit is asymmetric: most humans and primates tend to be better at horizontal than vertical smooth pursuit, as defined by their ability to pursue smoothly without making "catch-up saccades". Most humans are also better at downward than upward pursuit. Pursuit is modified by ongoing visual feedback.
Measurement.
There are two basic methods for recording smooth pursuit eye movements, and eye movement in general. The first is with a search coil. This technique is most common in primate research, and is extremely accurate. An eye movement shifts the orientation of the coil to induce an electric current, which is translated into horizontal and vertical eye position. The second technique is an eye tracker. This device, while somewhat more noisy, is non-invasive and is often used in human psychophysics and recently also in instructional psychology. It relies on the infrared illumination of the pupil to track eye position with a camera.
During oculomotor experiments, it is often important to ensure that no saccades occurred when the subject was supposed to be smoothly pursuing a target. Such eye movements are called catch-up saccades and are more common when pursuing at high speeds. Researchers are able to discard portions of eye movement recordings that contain saccades, in order to analyze the two components separately. Saccadic eye movements differ from the smooth pursuit component by their very high initial acceleration and deceleration, and peak velocity.
Neural circuitry.
The neural circuitry underlying smooth pursuit is an object of debate. The first step towards the initiation of pursuit is to see a moving target. Signals from the retina ascend through the lateral geniculate nucleus and activate neurons in primary visual cortex. Primary visual cortex sends the information about the target to the middle temporal visual cortex, which responds very selectively to directions of movement. The processing of motion in this area is necessary for smooth pursuit responses. This sensory area provides the motion signal, which may or may not be smoothly pursued. A region of cortex in the frontal lobe, known as the frontal pursuit area, responds to particular vectors of pursuit, and can be electrically stimulated to induce pursuit movements. Recent evidence suggests that the superior colliculus also responds during smooth pursuit eye movement. These two areas are likely involved in providing the "go"-signal to initiate pursuit, as well as selecting which target to track. The "go"-signal from the cortex and the superior colliculus is relayed to several pontine nuclei, including the dorsolateral pontine nuclei and the nucleus reticularis tegmenti pontis. The neurons of the pons are tuned to eye velocity and are directionally selective, and can be stimulated to change the velocity of pursuit. The pontine nuclei project to the cerebellum, specifically the vermis and the paraflocculus. These neurons code for the target velocity and are responsible for the particular velocity profile of pursuit. The cerebellum, especially the vestibulo-cerebellum, is also involved in the online correction of velocity during pursuit. The cerebellum then projects to optic motoneurons, which control the eye muscles and cause the eye to move.
Stages of smooth pursuit.
Pursuit eye movement can be divided into two stages: open-loop pursuit and closed-loop pursuit. Open-loop pursuit is the visual system's first response to a moving object we want to track and typically lasts ~100 ms. Therefore, this stage is "ballistic": Visual signals have not yet had time to correct the ongoing pursuit velocity or direction. The second stage of pursuit, closed-loop pursuit, lasts until the pursuit movement has ceased. This stage is characterized by the online correction of pursuit velocity to compensate for "retinal slip". In other words, the pursuit system tries to null retinal velocity of the object of interest. This is achieved at the end of the open-loop phase. In the closed-loop phase, the eye angular velocity and target angular velocity are nearly equal.
Smooth pursuit and spatial attention.
Various lines of research suggests a tight coupling for closed loop pursuit and spatial attention. For instance, during the close loop phase selective attention is coupled to the pursuit target such that untracked targets which move in the same direction with the target are poorly processed by the visual system. Recently, a loose coupling of open loop pursuit and attention was suggested, when there is only one possible moving target. This difference between pursuit and saccades may be accounted for by the differences in latency. Pursuit eye movements are initiated within 90-150 ms, while typical latencies for voluntary saccades are in the order of 200-250 ms
Smooth pursuit in the absence of a visual target.
Performing smooth pursuit without a moving visual stimulus is difficult, and typically results in a series of saccades. However, pursuit without a visible target is possible under some particular conditions, that show the importance of high-level functions in smooth pursuit maintenance.
If you know which way a target will move, or know the target trajectory (because it is periodic for instance), you can initiate pursuit before the target motion actually starts, especially if you know exactly when the motion will start.
It is also possible to maintain pursuit if a target momentarily disappears, especially if the target appears to be occluded by a larger object.
Under conditions in which there is no visual stimulation (in total darkness), we can still perform smooth pursuit eye movements with the help of a proprioceptive motion signal (e.g. your moving finger).
Following stimuli from peripheral gaze.
When a bright light appears in the periphery, the fastest it can achieve a smooth pursuit is 30°/second. It first fixes the gaze to the peripheral light, and if not in excess of 30°/second, will follow the target equally with the movement. At higher velocities, the eye will not move smoothly, and requires corrective saccades. Unlike saccades, this process uses a continuous feedback system, which is based strictly on error.
Distinction between smooth pursuit, optokinetic nystagmus, and ocular following response.
Although we can clearly separate smooth pursuit from the vestibulo-ocular reflex, we can not always draw a clear separation between smooth pursuit and other tracking eye movements like the slow phase of the optokinetic nystagmus and the ocular following response (OFR), discovered in 1986 by Miles, Kawano and Optican, which is a transient ocular tracking response to full-field motion. The latter are both slow eye movements in response to extended targets, with the purpose of stabilizing the image. Therefore, some processing stages are shared with the smooth pursuit system. Those different kinds of eye movements may not be simply differentiated by the stimulus that is appropriate to generate them, as smooth pursuit eye movements can be generated to track extended targets as well. The main difference may lie in the voluntary nature of pursuit eye movements.
Smooth-pursuit deficits.
Smooth pursuit requires the coordination of many brain regions that are far away from each other. This makes it particularly susceptible to impairment from a variety of disorders and conditions.
Schizophrenia.
There is significant evidence that smooth pursuit is deficient in people with schizophrenia and their relatives. People with schizophrenia tend to have trouble pursuing very fast targets. This impairment is correlated with less activation in areas known to play a role in pursuit, such as the frontal eye field. However, other studies have shown that people with schizophrenia show relatively normal pursuit, compared to controls, when tracking objects that move unexpectedly. The greatest deficits are when the patients track objects of a predictable velocity which begin moving at a predictable time. This study speculates that smooth pursuit deficits in schizophrenia are a function of the patients' inability to store motion vectors.
Autism.
People with autism show a plethora of visual deficits. One such deficit is to smooth pursuit. Children with autism show reduced velocity of smooth pursuit compared to controls during ongoing tracking. However, the latency of the pursuit response is similar to controls. This deficit appears to only emerge after middle adolescence.
Trauma.
People with post traumatic stress disorder, with secondary psychotic symptoms, show pursuit deficits. These patients tend to have trouble maintaining pursuit velocity above 30 degree/second. A correlation has also been found between performance on tracking tasks and a childhood history of physical and emotional abuse.
Drugs and Alcohol.
"Lack of Smooth Pursuit" is a scorable clue on the NHTSA's standardized field sobriety tests. The clue, in combination with others, may be used to determine if a person is impaired by alcohol and/or drugs. Drugs causing lack of smooth pursuit include depressants, some inhalants, and dissociative anesthetics (such as phencyclidine or ketamine).
Preterm Birth.
Children born very preterm show smooth pursuit deficits compared to paired controls born at full term. This delay in smooth pursuit has also been linked to later neurodevelopment in toddlerhood in children born very preterm.


Trap (printing)

In printing, trap expresses the degree to which ink already printed on a substrate accepts another layer printed on top of it compared to how well the substrate (e.g., paper) accepts that ink.
However, in the era of prepress software, the term came to refer to compensation for misregistration (when two layers of ink are not perfectly aligned) that was traditionally known as "chokes and spreads". Misregistration causes gaps or white-space on the final printed work. Correcting this involves creating overlaps (spreads) or underlaps (chokes) of objects during the print process.
Registration.
Misregistration in the graphical workflow may be caused by human error, inaccuracies in the image setter, the film-to-plate or film-to-film copying steps or instability of the image carrier (e.g., stretch in film or plate), the press or the final media.
These issues can be minimized, but not eliminated, given that any mechanical process produces some degree of error. However, the resulting gaps can be hidden by creating overlaps between two adjacent colors.
Methods.
In general, prepress software provides some level of trapping, via application default values. Additional trapping may be necessary.
Manual traps can be applied at several stages in the workflow, using vector-based or raster-based adjustments. The choice depends on the type of output (packaging applications including flexo-printing have other requirements than commercial printing on offset systems) and the degree of interactivity or automation.
In-RIP trapping moves the trapping to the Raster image processor (RIP) trapping at the last moment. The process is automatic, although it is possible to set up "zones" to allow different rules for different areas, or to disable trapping for areas already manually trapped.
Trapping decisions.
When the two colors in question are spot colors, trapping is always needed: from the moment the artwork is imaged on film or plate, the colors are handled separately and are printed on two different printing units. The same approach applies if one of the colors is a spot color and the other a process color.
Trapping becomes more difficult if both colors are process colors and each is to be printed as a combination of the basic printing colors cyan, magenta, yellow and black. In this case, the trapping decision depends on the amount of ‘common’ color.
Another factor that influences the visibility of the traps is the direction of the trap. The decision as to which color should be spread or choked is usually based upon their relative luminance. The lighter (higher luminance) color is spread into the darker. This responds to the way the human eye perceives color: darker colors define shapes, therefore distortion of the lighter color results in less visible distortion overall. The lightness or darkness of a color is defined as its neutral density.
A major exception to this is the case when opaque (colors that completely obscure colors printed beneath them) spot colors are used. Other colors, regardless of their relative luminance, are always trapped to (spread under) these spot colors. If several of these spot colors are used (a common practice in the packaging market), the order of printing layers rather than luminance is the decisive element: the first color to be printed is spread under the next color.
Thinner traps are less visible. Therefore, the trap width is set to a strict minimum, dictated by the maximum amount of misregistration of the entire workflow up to the press. When printing at 150 lpi, traps are usually between 1/150 and 1/300 inch (0.48 pt and 0.24 pt, 0.16 mm and 0.08 mm). These values are usually multiplied by 1.5 or 2 when one of the colors is black. The trap is not visible since the lighter color is spread underneath the—almost—opaque black. For the same reason, in many cases, black ink is set to "overprint" colors in the background, eliminating the more complex process of spreading or choking. Since black is a dark color, white gaps caused by misregistration are more visible. On top of that, in wet-in-wet offset printing, black is the first color to be printed, causing relatively more distortion, thus increasing the risk of visible misregistration.
When a trap between two colors is created, it contains the sum of the two colors in question when at least one of them is a spot color. When the two colors are process colors, the trap contains the highest value of each of the CMYK components. This trap color is always darker than the two abutting colors. In some cases, more specifically when the two colors are pastel-like colors, this might result in a trap that is perceived as too visible. In this case, reducing the amount of color in the trap may help. However, the trap should never be lighter than the darkest color since this would have the same effect as misregistration—creating a light colored ‘gap’ between the two colors. Trap color reduction is not recommended when solid spot colors are used. In that case, reduction would cause the spot color in the trap to be printed, not as a solid, but as a screened tint.
Trapping towards a rich black (a black with a support screen of another color added to it to give it a ‘deeper’ look and making it more opaque—often called "undercolor"), follows the same rules as trapping to a ‘normal’ black.
Blends or ‘vignettes’ offer special challenges to trapping. The lighter part of a blend needs to spread into the background, while the darker part needs to be choked. If a trap over the full length of the blend is needed, this produces a visible ‘staircase’ effect. The solution is to use a sliding trap: a trap that gradually changes both color and position. The trap can slide all the way. This might unacceptably distort the original artwork. Often, the sliding factor is set to a point where the neutral densities of blend and background reach an appropriate difference.


LSE (programming language)

LSE () is a programming language developed at Supélec and Télémécanique from the late 1960s to the mid 1970s.It is similar to BASIC, except with French-language instead of English-language keywords. It was derived from an earlier language called "LSD", also developed at Supélec. It is most commonly said to be an acronym for "Langage Symbolique d'Enseignement" (Symbolic Teaching Language), but other expansions are also known (e.g. "Langage de Sup-Élec", or the more cynical).
It originally flourished due to support from the French Ministry of National Education, but declined as the ministry lost interest. It went through a number of revisions; earlier versions of LSE lacked full support for structured programming, later versions such as LSE-83 (aka LSE-1983) by Jacques Arsac added structured programming support, along with exception handling. Even later revisions, such as LSE-2000, added more functionality, new types, new operators (NI, ET QUE, OU QUE and SELON-DANS-SINON), flow control commands, etc.
Code examples.
99 Bottles (AFNOR Z 65-020).
 1*CHANSON DES 99 BOUTEILLES DE BIERE
 2*PASCAL BOURGUIGNON, 2003
 10 FAIRE 20 POUR N←99 PAS -1 JUSQUA 1
 20 &STROF(N)
 30 AFFICHER['IL EST TEMPS D’’ALLER AU MAGASIN.',/]
 40 TERMINER
 100 PROCEDURE &STROF(N) LOCAL S1,S0;CHAINE S1,S0;S1←"S";S0←"S"
 110 SI N=2 ALORS S0←" SINON SI N=1 ALORS DEBUT S1←";S0←"" FIN
 120 AFFICHER[U,' BOUTEILLE',U,' DE BIERE SUR LE MUR.',/]N,S1
 130 AFFICHER[U,' BOUTEILLE',U,' DE BIERE.',/]N,S1
 140 AFFICHER['EN PRENDRE UNE, LA FAIRE PASSER.',/]
 150 AFFICHER[U,' BOUTEILLE',U,' DE BIERE SUR LE MUR.',2/]N-1,S0
 160 RETOUR
Anagrams (LSE-1983).
Example from Jacques Arsac in LSE83:
 1 CHAINE A,B,BP
 5 FAIRE
 10 AFFICHER 'A = ' ;LIRE A ; SI A=’’ ALORS FINI IS
 11 AFFICHER 'B = ' ;LIRE B ; BP ← B
 12
 15 R SI LGR(A) # LGR(B) ALORS .FAUX. SINON &ANAG(A,B) IS
 20 SI R ALORS AFFICHER A, 'EST ANAGRAMME DE ',BP
 21 SINON AFFICHER A, 'N’’EST PAS ANAGRAMME DE 1, BP
 22 IS
 25 BOUCLER
 29
 30 TERMINER
 31
 51 SI U=' ' ALORS RESULTAT .VRAI. IS
 52 SI J = 0 ALORS RESULTAT .FAUX. IS
 54 RESULTAT &ANAG(SCH(U,2, ' '),MCH(V,J,l, ' '))
 55 $&ANAG
 99 $
Largest common divisor, Euclid's algorithm (LSE2000).
 ** MÉTHODE D'EUCLIDE POUR TROUVER LE PLUS GRAND DIVISEUR COMMUN D'UN
 ** NUMÉRATEUR ET D'UN DÉNOMINATEUR.
 ** L. Goulet 2010
 PROCÉDURE &PGDC(ENTIER U, ENTIER V) : ENTIER LOCAL U, V
 ENTIER T
 TANT QUE U > 0 FAIRE
 SI U< V ALORS
 T←U
 U←V
 V←T
 FIN SI
 U ← U - V
 BOUCLER
 RÉSULTAT V
 FIN PROCÉDURE
 PROCÉDURE &DEMO(ENTIER U, ENTIER V) LOCAL U, V
 AFFICHER ['Le PGDC de ',U,'/',U,' est ',U,/] U, V, &PGDC(U,V)
 FIN PROCÉDURE
 &DEMO(9,12)


Pulitzer Prize for Commentary

The Pulitzer Prize for Commentary is an award administered by the Columbia University Graduate School of Journalism "for distinguished commentary, using any available journalistic tool". It is one of the fourteen American Pulitzer Prizes that are annually awarded for Journalism. It has been presented since 1970. Finalists have been announced from 1980, ordinarily with two others beside the winner.
Winners and citations.
The Commentary Pulitzer has been awarded to one person annually without exception—45 prizes in 44 years 1970–2014. No person has won it twice.
The New York Times and the Washington Post/Washington Post Writers Group are the media outlets associated with the most winners of the Pulitzer Prize for Commentary, with nine recipients each.


ASN Neuro

ASN Neuro is a peer-reviewed open access scientific journal covering neurochemistry. It is published by Sage Publications on behalf of the American Society for Neurochemistry, of which it is the official journal. The founding editor-in-chief was Anthony Campagnoni (University of California, Los Angeles), who was succeeded by Monica Carson (University of California, Riverside), and then in 2018 by Douglas L Feinstein (University of Illinois, Chicago).
Abstracting and indexing.
The journal is abstracted and indexed in Science Citation Index Expanded, BIOSIS Previews, Scopus, and Index Medicus/MEDLINE/PubMed. According to the "Journal Citation Reports", the journal has a 2017 impact factor of 3.617


Otic vesicle

Otic vesicle, or auditory vesicle, consists of either of the two sac-like invaginations formed and subsequently closed off during embryonic development. It is part of the neural ectoderm, which will develop into the membranous labyrinth of the inner ear. This labyrinth is a continuous epithelium, giving rise to the vestibular system and auditory components of the inner ear. During the earlier stages of embryogenesis, the otic placode invaginates to produce the otic cup. Thereafter, the otic cup closes off, creating the otic vesicle. Once formed, the otic vesicle will reside next to the neural tube medially, and on the lateral side will be paraxial mesoderm. Neural crest cells will migrate rostral and caudal to the placode.
The general sequence in formation of the otic vesicle is relatively conserved across vertebrates, although there is much variation in timing and stages. Patterning during morphogenesis into the distinctive inner ear structures is determined by homeobox transcription factors including PAX2, DLX5 and DLX6, with the former specifying for ventral otic vesicle derived auditory structures and the latter two specifying for dorsal vestibular structures.
Development.
The otic vesicle is derived from the cranial placode. The early otic vesicle is characterized as having broad competence and can be subdivided into sensory, non-sensory, and neurogenic components. Sensory epithelial cells and neurons are derived from the proneurosensory domain. This domain can be further sub-categorized into the neurogenic sub-domain and prosensory sub-domain. Prosensory sub-domain eventually gives rise to the support cells and hair cells while the neurogenic sub-domain gives rise to the auditory neuron and vestibular neuron.
The middle part of the otic vesicle develops into the ductus and saccus endolymphaticus. The anterior end of the otic vesicle gradually elongates as a tube and coils upon itself forming the beginnings of the cochlear duct. The vestibular extremity subsequently constricts to form the canalis reuniens. The central part of the otic vesicle represents the membranous vestibule, and is subdivided by a constriction into a smaller ventral part, the saccule, and a larger dorsal and posterior part, the utricle. The dorsal component of the inner ear also consists of what will become the semicircular canals. The utricle and saccule communicate with each other by means of a Y-shaped canal.
Gene signaling.
The FGF, Bmp, Wnt and Pax genes are likely to be involved in otic induction. FGF and BMP signals help control patterning in the early otic vesicle. Fgf3 and Fgf10 are suggested to play a role in otic induction in mice, as were Msx genes suggested to play a role in otic vesicle formation in chicks. Pax8 is expressed during the entirety of otic vesicle formation. Other genes found in the otic vesicle across species that may play a role in patterning include Hmx, Fox, Dlx, and Gbx genes.
Other animals.
Formation of the otic vesicle has been studied extensively in developmental model organisms including chicken, Xenopus, zebrafish, axolotl, and mouse. The transition from the otic placode to the otic vesicle occurs during the 19th somite stage in Zebrafish, Xenopus, and chick. In chick, invagination of the otic placode occurs passively due to the movements of the surrounding placode. The otic placode in zebrafish, on the other hand, occurs by cavitation; the ectodermal placode condenses and forms an ovoid ball directly below the embryo surface. Otic vesicle formation occurs later, during the 25-30 somite stage in mice.