Rostral ventromedial medulla

The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata (myelencephalon). The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons.
There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.
Involvement in neuropathic pain.
Research has shown the RVM to be important in the maintenance of neuropathic pain. Ablation of μ-opioid-expressing neurons in the RVM with a dermorphin-saporin conjugate reduced the duration of allodynia and hyperalgesia caused by a nerve injury. Treatment with the dermorphin-saporin conjugate did not alter baseline pain thresholds, or affect sensitivity in the first 5–10 days after nerve injury. This suggests that the RVM contributes to the persistent pathology caused by nerve injury.
Further research determined that a large majority of μ-opioid-expressing neurons also expressed CCK2 receptors. Microinjection in the RVM with either a CCK-saporin or a dermorphin-saporin conjugate eliminated neurons expressing either receptor. Injection of the CCK-saporin conjugate also reversed allodynia and hyperalgesia in a nerve injury model, producing the same results as the dermorphin-saporin conjugate. This destruction of neurons was relatively specific, as less than 10% of neurons in the RVM were destroyed. This suggests that the targeted neurons are the ones responsible for maintaining chronic neuropathic pain states, and that the observed effect was not due to diffuse destruction of RVM neurons.
In addition, lidocaine microinjections into the RVM temporarily reversed allodynia and hyperalgesia caused by nerve injury.
To help determine whether the persistent pain state was centrally or peripherally mediated, non-noxious stimuli were applied to the nerve-injured limb. In animals receiving vehicle injections into the RVM, there was an increase in c-Fos expression in the superficial and deep dorsal horn of the spinal cord, indicating activation of nociceptive neurons. Animals receiving the dermorphin-saporin conjugate into the RVM had significantly less c-Fos expression. This indicates that a persistent neuropathic pain state is centrally mediated.
Role of serotonin in pain modulation.
Serotonin receptors have been hypothesized to play a bidirectional role in the modulation of pain. Based on previous experiments, a 5-HT3 antagonist, ondansetron, and a 5-HT7 antagonist, SB-269,970, were chosen to study.
Systemic or intra-RVM injections of morphine produced dose-dependent antinociception. Spinal administration of SB-269970 reduced morphine-induced antinociception, whereas spinal administration of ondansetron had no effects. SB-269970 and ondansetron were then tested for their efficacy in reducing nociceptive responses. Allodynia and hyperalgesia were experimentally induced by administration of CCK into the RVM. Spinal administration of SB-269970 had no effect on nociception, whereas ondansetron completely reversed the effects of CCK injection. Spinal ondansetron also reversed allodynia and hyperalgesia caused by a peripheral nerve injury. Taken together, these findings indicate a role for 5-HT7 receptors in opioid-induced antinociception, and a role for 5-HT3 in pro-nociceptive facilitation.
One limiting factor is that SB-269970 was also found to be a potent α2-adrenergic antagonist. Since the study using SB-269970 did not use a
α2-adrenergic antagonist as a control, it is possible that some of the effects of SB-269970 are from its adrenergic effects.
Effects of Substance P and Neurokinin 1 receptors.
The RVM contains high levels of both the neurokinin 1 receptor and its endogenous ligand, Substance P (SP). Microinjections of SP into the RVM resulted in transient antinociception to noxious heat stimuli but not mechanical stimuli. Pretreatment with a neurokinin 1 (NK1) antagonist prevented the antinociception induced by SP injection, but the NK1 antagonist had no effects on pain threshold by itself. To test the effects of an NK1 antagonist during injury states, an NK1 antagonist was microinjected into the RVM after application of Freund's Complete Adjuvant (CFA), a chemical used for inflammation models. Administration of the NK1 antagonist reversed the heat hyperalgesia caused by CFA. In contrast, the administration of an NK1 antagonist further increased the tactile hyperalgesia induced by CFA. However, the NK1 antagonist did prevent some tactile hyperalgesia induced by a different compound, capsaicin. In yet another induced injury model using mustard oil (a TRPA1 agonist), NK1 antagonists did not affect thermal or tactile hyperalgesia.
In contrast to the study above, another group of researchers found that microinjection of SP into the RVM resulted in transient thermal hyperalgesia, which persisted long-term when continuous infusion pumps were implanted. To look more at the SP-NK1 signaling, they performed Western Blots of RVM slices, looking for NK1 receptor expression. NK1 receptor expression was increased from 2 hours to 3 days after administration of CFA.
NK1 agonism induced hypersensitivity is dependent on 5-HT3 receptors, and modulated by GABAA and NMDA receptors as well. Animals were pretreated with spinally administered Y-25130 or ondansetron, both 5-HT3 antagonists, before having RVM injections of SP. Both Y-25130 and ondansetron inhibited SP-induced thermal hyperalgesia. GABAA receptor involvement was demonstrated by intrathecal administration of gabazine, a GABAA antagonist, in animals receiving continuous infusions of SP into the RVM. Gabazine treatment completely reversed the thermal hyperalgesia. The mechanism behind GABA involvement was investigated using in vitro recordings from animals treated with continuous infusions of SP or saline into the RVM. In SP-treated neurons, GABA evoked depolarization, whereas, in saline-treated neurons, it caused hyperpolarization. "These results suggest that descending facilitation induced by RVM SP administration produces GABAA receptor-evoked depolarization and an increase in excitation of dorsal horn neurons." Next, the GABA A agonist muscimol was tested in conjuncture with SP. Intrathecal muscimol significantly enhanced SP-induced hypersensitivity, which was blocked by intrathecal gabazine. Next, the researchers looked at threonine phosphorylation of NKCC1 proteins, which are an isoform of the Na-K-Cl cotransporter. Phosphorylation of these proteins results in increase activity of the cotransporter. Chronic administration of RVM SP or acute SP combined with intrathecal muscimol resulted in significantly higher levels of phosphorylated NKCC1.
Involvement of NMDA receptors.
The role of NMDA receptors in non-inflammatory noxious stimuli was examined. The injury model consisted of two injections of acidic saline (pH = 4.0), and was designed to model non-inflammatory muscular pain. Intra-RVM administration of AP5 or MK-801, NMDA receptor antagonists, resulted in a reversal of the mechanical sensitivity induced by the acidic saline.
Behavioral hyperalgesia in inflammatory pain states is closely correlated with phosphorylation of spinal NMDA receptors. To find out more about the role of NMDA receptors in RVM pain facilitation, intrathecal MK-801 was administered before a RVM SP injection. Pretreatment with MK-801 significantly reduced SP induced hyperalgesia. Intrathecal MK-801 also blocked hyperalgesia resulting from continuous SP infusions. SP also increased the phosphorylation of the NR1 subunit of NMDA receptors.
In order to find out the relationship between GABA, NMDA, and SP, MK-801 was administered intrathecally to determine the effect on muscimol potentiation of SP hyperalgesia. MK-801 reduced the exaggeration of SP hyperalgesia induced by muscimol. Also, low doses of SP and intrathecal muscimol increased the expression of phosphorylated NR1 subunits of NMDA receptors. Intrathecal gabazine treatment before muscimol blocked the increase in phosphorylated NR1 expression.
Purinergic involvement.
On- and off-cells were both activated by local administration of ATP, a P1 and P2 agonist, whereas neutral cells were inhibited. However, on-cells and off-cells differed in their response to P2X and P2Y agonists.
On-cells displayed a greater response to P2X agonists vs P2Y agonists. For example, α,β-methylene ATP, a P2X agonist, activated all on-cells, whereas 2-methylthio-ATP, a P2Y agonist, activated only 60% of on-cells tested. All on-cells showed a response to the non-specific P2 agonist uridine triphosphate (UTP). Activation of on cells by ATP was reversed by using the P2 antagonists suramin and pyridoxal-phosphate-6-azophenyl-2′,4′disulphonic acid (PPADS), but not with the P2Y antagonist MRS2179.
In contrast, off-cells were more responsive to P2Y agonists. 2-Methylthio-ATP activated all off-cells, whereas α,β-methylene ATP, a P2X agonist, activated only one-third of off-cells. Off-cells were also activated by UTP, but lacked any response to adenosine, a P1 agonist. Activation of off-cells by ATP was inhibited by suramin, PPADS, and MRS2179.
Neutral cells are inhibited by adenosine, a P1 agonist, whereas on-cells and off-cells lack a response to adenosine.
Histological staining by another research group examined the distribution of purinergic receptor subtypes throughout the RVM. P1, P2X1, and P2X3 all showed moderate labeling density, with slightly greater densities observed in the nucleus raphes magnus and the raphe pallidus. In contrast, P2Y1 showed lower levels of labeling. P1 and P2Y1 were shown to be co-localized, as well as P2X1 and P2Y1. Presence of the raphe nuclei in the RVM also led to staining for tryptophan hydroxylase (TPH), a marker for serotonin (5-HT) positive neurons, and looking for co-localization of 5-HT neurons with purinergic receptors. Only about 10% of RVM neurons were TPH positive, but, of those labeled for TPH, a large majority were co-labeled with purinergic antibodies. Fifty-five percent of TPH+ neurons stained for P1, 63% for P2X1, 64% for P2X3, and 70% P2Y1.


GJA4

Gap junction alpha-4 protein, also known as Connexin-37 or Cx37, is a protein that in humans is encoded by the "GJA4" gene. This protein, like other Connexin proteins, forms connections between cells known as gap junctions. Connexin 37 can be found in many tissues including the ovary, heart, and kidney.


Dorsal ramus of spinal nerve

The dorsal ramus of spinal nerve (or posterior ramus of spinal nerve, or posterior primary division) is the posterior division of a spinal nerve. The dorsal ramus (Latin for branch, plural "rami" ) is the dorsal branch of a spinal nerve that forms from the dorsal root of the nerve after it emerges from the spinal cord. The spinal nerve is formed from the dorsal and ventral rami. The dorsal ramus carries information that supplies muscles and skin sensation to the human back.
Structure.
Shortly after a spinal nerve forms from the dorsal and ventral roots of the spinal cord it branches into the dorsal ramus and ventral ramus. Spinal nerves are mixed nerves that carry both sensory and motor information. It also branches to form the grey and the white rami communicantes which make connections with the sympathetic ganglia.
After it is formed, the dorsal ramus of each spinal nerve travels backward, except for the first cervical, the fourth and fifth sacral, and the coccygeal. Dorsal rami divide into medial, intermediate, and lateral branches. The lateral branch supplies innervation to the iliocostalis muscle, as well as the skin lateral to the muscle on the back. The Intermediate branch supplies innervation to the spinalis muscle and the longissimus muscle. The medial branch supplies innervation to the rest of the epaxial derived muscles on the back (including the transversospinales, intertransversarii muscles, interspinalis muscles, suboccipital muscles, and splenius), and the zygapophyseal joints.
Function.
Because each spinal nerve carries both sensory and motor information, spinal nerves are referred to as mixed nerves. Posterior rami carry visceral motor, somatic motor, and sensory information to and from the skin and deep muscles of the back. The posterior rami remain distinct from each other, and each innervates a narrow strip of skin and muscle along the back, more or less at the level from which the ramus leaves the spinal nerve.


Cortical column

A cortical column, also called hypercolumn, macrocolumn, functional column or sometimes cortical module, is a group of neurons in the cortex of the brain that can be successively penetrated by a probe inserted perpendicularly to the cortical surface, and which have nearly identical receptive fields. Neurons within a minicolumn (microcolumn) encode similar features, whereas a hypercolumn "denotes a unit containing a full set of values for any given set of receptive field parameters". A cortical module is defined as either synonymous with a hypercolumn (Mountcastle) or as a tissue block of multiple overlapping hypercolumns.
The columnar hypothesis states that the cortex is composed of discrete, modular columns of neurons, characterized by a consistent connectivity profile.
It is still unclear what precisely is meant by the term, and it does not correspond to any single structure within the cortex. It has been impossible to find a canonical microcircuit that corresponds to the cortical column, and no genetic mechanism has been deciphered that designates how to construct a column. However, the columnar organization hypothesis is currently the most widely adopted to explain the cortical processing of information.
Mammalian cerebral cortex.
The mammalian cerebral cortex, the grey matter encapsulating the white matter, is composed of layers. The human cortex is between 2 and 3 mm thick. The number of layers is the same in most mammals, but varies throughout the cortex. In the neocortex 6 layers can be recognized although many regions lack one or more layers, fewer layers are present in the archipallium and the paleopallium.
Columnar functional organization.
The columnar functional organization, as originally framed by Vernon Mountcastle, suggests that neurons that are horizontally more than 0.5 mm (500 µm) from each other do not have overlapping sensory receptive fields, and other experiments give similar results: 200–800 µm. Various estimates suggest there are 50 to 100 cortical minicolumns in a hypercolumn, each comprising around 80 neurons. Their role is best understood as 'functional units of information processing.'
An important distinction is that the columnar organization is functional by definition, and reflects the local connectivity of the cerebral cortex. Connections "up" and "down" within the thickness of the cortex are much denser than connections that spread from side to side.
Hubel and Wiesel studies.
David Hubel and Torsten Wiesel followed up on Mountcastle's discoveries in the somatic sensory cortex with their own studies in vision. A part of the discoveries that resulted in them winning the 1981 Nobel Prize was that there were cortical columns in vision as well, and that the neighboring columns were also related in function in terms of the orientation of lines that evoked the maximal discharge. Hubel and Wiesel followed up on their own studies with work demonstrating the impact of environmental changes on cortical organization, and the sum total of these works resulted in their Nobel Prize.
Number of Cortical columns.
There are about 100,000,000 cortical minicolumns in the neo-cortex with up to 110 neurons each, giving 1,000,000–2,000,000 cortical columns. There may be more if the columns can overlap, as suggested by Tsunoda "et al".
Updated information: it's not a scientific consensus now that "There are about 100,000,000 cortical minicolumns in the neo-cortex with up to 110 neurons each," as the original research is too arbitrary in many ways: the authors just chose a fixed width and length to calculate the cell numbers. They mainly use the number to propose that the neocortex is uniform, but later research pointed out that the neocortex is indeed not uniform by studying nine primate species and found that " the number of neurons underneath 1 mm2 of the cerebral cortical surface" "varies by three times across species." So now it is common sense that the neocortex is not uniform. The number of neurons within a single column is a variable, which depends on the existence of cortical columns in certain brain areas and on the definition of the column.


Mesostriatal system

The Mesostriatal system is a term sometimes used to identify the midbrain dopamine projections into the striatum and cortex. It has been described as a combination of the mesolimbic and nigrostriatal dopamine projections, and has been described as being partially asymmetric.
Research.
It has been referred to in the context of α-melanocyte stimulating hormones effect on dopamine activity in the mesostriatal system. Research identifying cholinergic projections into these mesostriatal nuclei have been performed, revealing that the midbrain dopaminergic nuclei receive projections from the pedunculopontine tegmentum and laterodorsal pontine tegmentum. The mesostriatal system has also been implicated in reward learning, coding predictions. This anatomical classification has also been used in the context of parkinson research.


Eddie Carroll

Eddie Carroll (September 5, 1933 – April 6, 2010) was a Canadian-American actor and voice actor, who is best known as the third performer to provide the voice for Jiminy Cricket, a role he played for over 35 years.
Career.
In Canada he studied at the Orion theater with fellow student Robert Goulet. After moving to Hollywood in 1956 to work for NBC as a writer and producer, living as a resident alien in the United States, he was drafted into the US Army. He performed with the Armed Forces Radio Service and the 6th Army Chorus. In 1959 he took the professional name Eddie Carroll. In 1960 Carroll released a comedy album, "On Fraternity Row." In 1962 he co-wrote the song "How Is Julie?" which was recorded by The Lettermen. Starting in the early 1960s Carroll appeared in numerous television programs and commercials. In 1970, he and business partner Jamie Farr developed and syndicated a sports-talk program, "Man to Man", through MGM Television, and not long after a Saturday morning animated series for Hanna-Barbera, "The Amazing Chan and the Chan Clan".
He took over the role of Jiminy Cricket for Walt Disney Productions in 1973 after the death of original voice actor Cliff Edwards in 1971, and a brief stint by Clarence Nash. From 1983 until his death in 2010 Carroll traveled with two one-man shows portraying comedian Jack Benny: "A Small Eternity with Jack Benny" and "Jack Benny: Laughter in Bloom." In 1995–96 he toured with a production of "The Odd Couple". In later years, he attended numerous conventions and gatherings for both Disney fans and devotees of old-time radio.
Eddie Carroll was sometimes billed as Eddy Carroll. He is not to be confused with British big band musician Eddie Carroll.
Personal life.
Carroll married his wife Carolyn Springer (d. January 8, 2018) on April 7, 1963; together they had two children, Tina and Leland.
Death.
Carroll died on April 6, 2010 of a brain tumor at the Motion Picture & Television Country House and Hospital in Woodland Hills, California, at the age of 76. just one day before his 47th wedding anniversary.


Pull to par

Pull to Par is the effect in which the price of a bond converges to par value as time passes. At maturity the price of a debt instrument in good standing should equal its par (or face value).
Another name for this effect is reduction of maturity.
It results from the difference between market interest rate and the nominal yield on the bond.
The Pull to Par effect is one of two factors that influence the market value of the bond and its volatility (the second one is the level of market interest rates).


Society for Behavioral Neuroendocrinology

The Society for Behavioral Neuroendocrinology is an interdisciplinary scientific organization dedicated to the study of hormonal processes and neuroendocrine systems that regulate behavior.
Publications.
SBN publishes the scientific journal "Hormones and Behavior".


F wave

In neuroscience, an F wave is one of several motor responses which may follow the direct motor response (M) evoked by electrical stimulation of peripheral motor or mixed (sensory and motor) nerves. F-waves are the second of two late voltage changes observed after stimulation is applied to the skin surface above the distal region of a nerve, in addition to the H-reflex (Hoffman's Reflex) which is a muscle reaction in response to electrical stimulation of innervating sensory fibers. Traversal of F-waves along the entire length of peripheral nerves between the spinal cord and muscle, allows for assessment of motor nerve conduction between distal stimulation sites in the arm and leg, and related motoneurons (MN's) in the cervical and lumbosacral cord. F-waves are able to assess both afferent and efferent loops of the alpha motor neuron in its entirety. As such, various properties of F-wave motor nerve conduction are analyzed in nerve conduction studies (NCS), and often used to assess polyneuropathies, resulting from states of neuronal demyelination and loss of peripheral axonal integrity.
With respect to its nomenclature, the F-wave is so named as it was initially studied in the smaller muscles of the foot. The observation of F-waves in the same motor units (MU) as those present in the direct motor response (M), along with the presence of F-waves in deafferented animal and human models, indicates that F-waves require direct activation of motor axons to be elicited, and do not involve conduction along afferent sensory nerves. Thus, the F-wave is considered a wave, as opposed to a reflex.
Physiology.
F-waves are evoked by strong electrical stimuli (supramaximal) applied to the skin surface above the distal portion of a nerve. This impulse travels both in orthodromic fashion (towards the muscle fibers) and antidromic fashion (towards the cell body in the spinal cord) along the alpha motor neuron. As the orthodromic impulse reaches innervated muscle fibers, a strong direct motor response (M) is evoked in these muscle fibers, resulting in a primary compound muscle action potential (CMAP). As the antidromic impulse reaches the cell bodies within the anterior horn of the motor neuron pool by retrograde transmission, a select portion of these alpha motor neurons, (roughly 5-10% of available motor neurons), 'backfire' or rebound. This antidromic 'backfiring' elicits an orthodromic impulse that follows back down the alpha motor neuron, towards innervated muscle fibers. Conventionally, axonal segments of motor neurons previously depolarized by preceding antidromic impulses enter a hyperpolarized state, disallowing the travel of impulses along them. However, these same axonal segments remains excitable or relatively depolarized for a sufficient period of time, allowing for rapid antidromic backfiring, and thus the continuation of the orthodromic impulse towards innervated muscle fibers. This successive orthodromic stimulus then evokes a smaller population of muscle fibers, resulting in a smaller CMAP known as an F-wave.
Several physiological factors may possibly influence the presence of F-waves after peripheral nerve stimulation. The shape and size of F-waves, along with the probability of their presence is small, as a high degree of variability exists in motor unit (MU) activation for any given stimulation. Thus, the generation of CMAP's which elicit F-waves is subject to the variability in activation of motor units in a given pool over successive stimuli. Moreover, stimulation of peripheral nerve fibers account for both orthodromic impulses (along sensory fibers, towards the dorsal horn), as well as antidromic activity (along alpha motor neurons towards the ventral horn). Antidromic activity along collateral branches of alpha motor neurons may result in the activation of inhibitory Renshaw cells or direct inhibitory collaterals between motorneurons. Inhibition by these means may lower excitability of adjacent motor neurons and decrease the potential for antidromic backfiring and resultant F-waves; although it has been argued Renshaw cells preferentially inhibit smaller alpha motor neurons limited influence on modulation of antidromic backfiring.
Because a different population of anterior horn cells is stimulated with each stimulation, F waves are characterized as ubiquitous, low amplitude, late motor responses, which can vary in amplitude, latency and configuration across a series of stimuli.
Properties.
F waves can be analyzed by several properties including:
Measurements.
Several measurements can be done on the F responses, including:
The minimal F wave latency is typically 25-32 ms in the upper extremities and 45-56 ms in the lower extremities.
F wave persistence is the number of F waves obtained per the number of stimulations, which is normally 80-100% (or above 50%).


Type Ia sensory fiber

A type Ia sensory fiber, or a primary afferent fiber is a type of afferent nerve fiber. It is the sensory fiber of a stretch receptor called the muscle spindle found in muscles, which constantly monitors the rate at which a muscle stretch changes. (In other words, it monitors the velocity of the stretch).
Function of muscle spindles.
For the body to keep moving properly and with finesse, the nervous system has to have a constant input of sensory data coming from areas such as the muscles and joints. In order to receive a continuous stream of sensory data, the body has developed special sensory receptors called proprioceptors. Muscle spindles are a type of proprioceptor, and they are found inside the muscle itself. They lie parallel with the contractile fibers. This gives them the ability to monitor muscle length with precision.
Types of sensory fibers.
This change in length of the spindle is transduced (transformed into electric membrane potentials) by two types of sensory afferents, whose cell bodies are located in dorsal root ganglia located next to the spinal cord.
The two kinds of sensory fibers are different with respect to the kind of potentials they generate:
The first of the two main groups of stretch receptors wrapping the intrafusal fibers are the Ia fiber, which are the largest and fastest fibers, and they fire when the muscle is stretching. They are characterized by their rapid adaptation, because as soon as the muscle stops changing length, the Ia stop firing and adapt to the new length. Ia fibers essentially supply proprioceptive information about the "rate of change" of its respective muscle: the derivative of the muscle's length (or position).
Type Ia fibers connect to both nuclear bag fibers and nuclear chain fibers. These connections are also called "annulospiral endings", deriving from the Latin word "annulus" which means "a ring-shaped area or structure".
Efferent innervation.
In addition, the spindle also has a motor efferent innervation carried by the efferent nerve fibers of gamma motor neurons, which is used by the nervous system to modify the spindle's sensitivity.
Termination of afferents.
Proprioceptive afferents send central axons through the dorsal root of spinal nerve bifurcating into ascending and descending branches, which in turn send branches to multiple spinal segments. Some branches synapse at the dorsal horn and some at the ventral horn (where the motor neurons are) which mediate different responses including stretch reflex. Ascending pathways to the brain have some similarities with the cutaneous afferents, but are different because the proprioceptive information also has to reach the cerebellum which controls the timings of muscle contractions for voluntary movements.


Midbrain reticular formation

The midbrain reticular formation (MRF) also reticular formation of midbrain, mesencephalic reticular formation, tegmental reticular formation, formatio reticularis (tegmenti) mesencephali) is a structure in the midbrain consisting of the dorsal tegmental nucleus, ventral tegmental nucleus, and cuneiform nucleus. These are also known as the tegmental nuclei.
The dorsal and ventral tegmental nuclei receive connections from the mammillo-tegmental "bundle of Gudden", a branch of the mammillothalamic tract. The bundle of Gudden might be identical to the hypothalamotegmental tract.
Along with the oral pontine reticular nucleus, the midbrain reticular formation projects to the gigantocellular reticular nucleus.
The midbrain reticular formation is the point at which the different algedonic signals come together, ensuring that the organism is aware of potential threats.


Splatoon 2

Splatoon 2 is a 2017 third-person shooter game developed and published by Nintendo for the Nintendo Switch. It was released on July 21, 2017 and is a direct sequel to "Splatoon", which includes a new story-driven single-player mode and various online multiplayer modes. An expansion pack for the single-player mode titled "" was subsequently released as downloadable content (DLC) in June 2018.
The game received generally positive reviews upon release. As of March 2021, "Splatoon 2" had sold over 12.21 million copies worldwide, selling more than twice as many as its predecessor and making it one of the best-selling Switch games. A sequel, "Splatoon 3", is set to release for the Nintendo Switch in 2022.
Gameplay.
Like its predecessor, "Splatoon 2" is a third-person shooter in which players control characters, known as Inklings and Octolings, and use colored ink as ammunition. Ink is also used to cover the ground, or any paintable surface, in order to swim or refill their ink tanks. Inklings and Octolings can morph between humanoid, or kid form, where they switch from walking and shooting, into squid form where they can quickly swim through ink of their own color, and replenish their ink supply, as well as return to full health.
The sequel adds new standard, sub and special weapons, including dual-wield pistols called Dualies that allow the player to perform dodge rolls, shotgun-like weapons called Brellas that enable defensive maneuvers with folding shields, and jetpacks known as Inkjets. Like the previous game, it features the standard Turf War mode for Regular Battles, in which two four-player teams have three minutes to cover the most turf with their color of ink. "Splatoon 2" also maintains the first game's rotation of Splat Zones, Tower Control and Rainmaker for Ranked Battles, unlocked at level ten, while also adding a new Clam Blitz mode. League Battles allow players to form teams with friends playing the same modes as in Ranked Battles. A new mode, Salmon Run, allows up to four players to team up cooperatively to tackle waves of enemies called Salmonids and collect Boss Salmonids' eggs.
Once per month until July 2019, a "Splatfest" event was held in which players could choose one of two teams, usually based on common debates such as heroes versus villains and pancakes versus waffles. In addition, there were two collaborations during these Splatfests: Nickelodeon's "Rise of the Teenage Mutant Ninja Turtles" and "Super Smash Bros. Ultimate". Splatfest themes were usually announced two weeks in advance, and players were given the ability to choose their team in the game's lobby. Themes were usually region-specific and happen at different times of the month. The only mode available in a Splatfest was Turf War, but players could choose between normal and pro modes. Winning battles awarded 'clout' to the winning team, and at the end of the Splatfest, the winning side was decided by evaluating popularity and clout earned in both battle modes. All players who participate earn rare rewards, but players on the winning team receive a slightly higher cut. In July 2019, Nintendo announced that the final regular Splatfest would be held that month. However, bonus rematches of previous Splatfests were held in May 2020, August 2020, and October 2020. A Splatfest celebrating the Super Mario Bros. 35th Anniversary was held in January 2021.
The game features a single-player campaign called Hero Mode, in which the player rescues captured Zapfish across various levels while fighting off evil Octarians. Unlike the previous game's single-player campaign which had a pre-determined weapon set, the player can now earn various weapons, some of which are required when playing levels for the first time. In addition to Sunken Scrolls that unlock artwork and in-game lore, players can collect Power Orbs to upgrade their Hero Mode weapons, and tickets that can be exchanged for temporary reward boosts in multiplayer battles, such as increased experience or in-game money. Using a single weapon to beat all of the Hero Mode levels grants the player a Hero Weapon Replica (identical to the campaign weapon) to use in multiplayer matches. In the "Octo Expansion" DLC, players play as an Octoling in a new single-player campaign featuring eighty missions in which the player teams up with Inkopolis veteran Cap’n Cuttlefish, as well as the fictional in-game pop band known as Off The Hook, which consists of the characters Pearl and Marina, to collect assorted items called “Thangs”, as well as defeat enemies along the way. Players can also play multiplayer online through an internet connection or play locally, although local play requires multiple consoles and copies of the game. The game also features LAN support with an adapter accessory for local private tournaments. The game supports amiibo figures, which allow players to store their character's custom look and unlock additional content. Free post-release updates and events are ongoing.
Plot.
"Splatoon 2" takes place approximately two years after the final Splatfest event of the first game, in which the pop idol Marie defeated her cousin and fellow Squid Sister, Callie. After having drifted apart in the months following the event, Marie worries that Callie was negatively affected by the result. After leaving Inkopolis to see her parents, Marie returns home to discover that the Great Zapfish that powers the city has gone missing again, as has Callie. Fearing that the evil Octarians are once more involved, Marie again takes up her role as Agent 2 of the New Squidbeak Splatoon and recruits an Inkling from Inkopolis Square, the player character, to become Agent 4 and investigate.
With assistance from Marie and weapons expert Sheldon, Agent 4 makes their way through Octo Canyon fighting Octarians and recovering several stolen Zapfish, including ones powering the Octarians' war machines, such as the Octo Oven, the Octo Samurai and the Octo Shower. They discover that Callie herself has sided with the Octarians after being brainwashed by their leader, DJ Octavio, who has escaped his imprisonment after his defeat in the first game and once more is using the Great Zapfish to power his new DJ stage, the Octobot King II. Marie arrives with Sheldon and frees Callie from her mind control, and together they help Agent 4 defeat Octavio once more. With the Great Zapfish safely returned to Inkopolis, the Squid Sisters happily reunite and resume their musical career with the song "Fresh Start".
Release.
A limited-time global multiplayer demo for the game, known as the ""Splatoon 2" Global Testfire", was released in March 2017. A special edition of Nintendo Treehouse Live was streamed during the first session, in which members of the Nintendo Treehouse participated in the demo. Similarly to the demo of the original game, it was only available to play for a specific time period, across six one-hour play sessions in one weekend. Another demo session demonstrating the game's Splatfest events was held on July 15, 2017.
The game was released worldwide on July 21, 2017. In Japan and Europe, neon-green and neon-pink Joy-Con controllers and "Splatoon"-themed Pro Controllers were released alongside the game. A game card-free version, which features a download code inside a game case instead of a game card, was also released in Japan, as well as a Switch hardware bundle including a download code for the game. A similar bundle was released in the United States as a Walmart exclusive.
New Amiibo figures of new Inkling Girl, Boy and Squid designs from "Splatoon 2" were released alongside the game. These figures, alongside previous "Splatoon" figures, unlock exclusive in-game clothing and music tracks and allow the player to save a loadout of weapons and clothing to the figure so they can be readily accessed at any time. Characters with these saved load-outs can be posed alongside the player for taking screenshots. Amiibo figures of Pearl and Marina from Off the Hook were released on July 13, 2018, and feature similar functionality to those already released, while a final trio of figures of Octoling Girl, Boy and Octopus designs were released in Japan and Europe on November 9, 2018, and in North America on December 7, 2018.
Like the previous game, "Splatoon 2" was continually updated post-release with free content. From launch, at least one new weapon was added to the game almost every week, while new stages and game modes were added at irregular intervals. In late April 2018, this changed to having a large group of weapons added every month instead, with new stages continuing to be added until October 2018. While these regular updates were originally due to continue for around a year after the game's launch, with monthly regional Splatfest events being held for around two years, the regular updates were later extended to last until the end of 2018. An expansion pack for the game's single-player mode, titled "Octo Expansion", was released in June 13, 2018.
The game's content update in December 2018 was announced as the final one, albeit with balancing patches and Splatfest events due to continue into Summer 2019, but it was later revealed that more smaller updates would release until July 2019.
Promotion.
Prior to "Splatoon 2"s reveal, clips of the game were featured in the announcement trailer for the Nintendo Switch. Its unanticipated appearance led to speculation by the media and public over whether or not the footage shown was that from a port of "Splatoon" or a sequel. It was also presented in the trailer in a way that promoted the game as an eSport, following investments by Nintendo in "Splatoon" eSport tournaments in late 2016.
"Splatoon 2" was officially unveiled to the public during the Nintendo Switch reveal presentation held in Tokyo on January 13, 2017, where it was announced for release in Q2/Q3 2017. The reveal was accompanied by a trailer featuring the game's new maps and weapons, and an on-stage appearance of producer Hisashi Nogami in-character as a scientist from the Squid Research Lab, a fictional scientific group from the game, which appeared in various promotional material for the original "Splatoon".
Similarly to the first game, "Splatoon 2" features Splatfest events that include crossovers with other brands, both from other Nintendo properties such as "Super Smash Bros. Ultimate" and third-party franchises including Teenage Mutant Ninja Turtles, McDonald's, Uniqlo, Nike, Sanrio, Meiji, and Pocky.
Other media.
A manga series based on the game and illustrated by Sankichi Hinodeya began serialization in Shogakukan's "CoroCoro Comic" magazine in May 2017. It was published in North America by Viz Media in late 2017. A motion comic adaptation of the manga was announced in July 2017 and released on YouTube the following month.
"Splatune 2", a two-disc official soundtrack featuring music from the game by Toru Minegishi, Ryo Nagamatsu, and Shiho Fujii, was published by Enterbrain in Japan on November 29, 2017, debuting at number eight on "Billboard Japan" Hot Albums chart. A second soundtrack album, "Octotune," was released in Japan on July 18, 2018. This album features tracks added in the game's "Octo Expansion" DLC and other post-release updates, as well as a recording of the game's first live concert. It peaked at number five on the Hot Albums chart.
Similarly to the first game, a series of real-life virtual concerts featuring the game's signature band Off the Hook have been performed in various locations. Their first concert was held at Tokaigi 2018 in Japan on February 10, 2018, a second was performed at Polymanga in Switzerland on March 31, 2018, a third concert which featured a new song, "Nasty Majesty" from "Splatoon 2"s "Octo Expansion", was performed at NicoNico Chokaigi in Japan on April 28, 2018, a fourth concert was performed at Tokaigi Game Party 2019 in Japan on January 26, 2019, which featured more songs from the "Octo Expansion", and was the first concert to only feature Pearl and Marina, and a two day concert featuring both the Squid Sisters and Off The Hook was performed at Nintendo Live 2019 on October 13–14, 2019, which featured performances based on previous concerts.
Reception.
"Splatoon 2" received "generally favorable" reviews, according to review aggregator Metacritic. Critics stated that "Splatoon 2" retained what was great about the original game while adding new features to keep the game fresh. "Nintendo Life" praised the improved single-player campaign. "Destructoid" and "Game Informer" criticised the accessibility within the game's multiplayer modes—weapons couldn't be changed between matches at that time (though this was added in a later update), no split-screen play, and the Salmon Run mode is only playable online at certain times—but praised the new weapons and gameplay. "The Verge" blamed the lack of a built-in voice chat feature and ease of viewing the map for taking away from the multiplayer experience, yet still calling the game an improvement over the original. GameSpot cited "Splatoon 2" as "a fresh take on the already unique shooter" but pointed out that using a mobile app for voice communication made multiplayer more complicated than it needed to be. Game Revolution and GamesRadar both praised the colorful artstyle and depth of the multiplayer combat. IGN gave the game a score of 8.3/10—higher than the initial score of the original game but lower than its re-review—praising the "addicting" Salmon Run mode and improved graphics, while making similar complaints about the game's matchmaking system. "Electronic Gaming Monthly" and Nintendo World Report both stated that the game felt "more like "Splatoon 1.5"" than a true sequel to the original, but nonetheless complimented the game's new additions.
"Eurogamer" ranked the game 17th on their list of the "Top 50 Games of 2017", while "Polygon" ranked it 43rd on their list of the 50 best games of 2017. "The Verge" named "Splatoon 2" as one of their 15 Best Games of 2017. The game was nominated for "Best Switch Game" in both "Destructoid"s Game of the Year Awards 2017 and IGN's Best of 2017 Awards, the latter of which also nominated it for "Best Shooter" and "Best Multiplayer".
Sales.
"Splatoon 2" debuted second on the UK software sales chart in its launch week, behind "Crash Bandicoot N. Sane Trilogy". It had 59% better first week sales than "Splatoon" and became the third biggest launch of a Switch game in that country. In Japan, "Splatoon 2" sold roughly 648,000 copies at retail within the first few days of its launch. Including download copies, the game had sold over two million in Japan by early 2018, making it the first home console game to do so in the country since 2010's "Wii Party". The game shipped 1.56 million copies in Japan and 3.61 million copies worldwide in its first fiscal quarter on sale. By June 2020, the game had sold 10.71 million copies worldwide, making it the ninth best-selling Switch game worldwide. As of March 2021, "Splatoon 2" had sold over 12.21 million copies worldwide, selling twice as much as its predecessor, and making it one of the best-selling Switch games.
Sequel.
On February 17, 2021, during a Nintendo Direct, Nintendo announced a teaser trailer for "Splatoon 3", also being released for the Switch and is set to be released in 2022. The teaser trailer revealed gameplay similar of which to "Splatoon 2", and revealed new items, weapons, and abilities, inculding an Ink Bow and a new apocalyptic design.


Unipolar neuron

A unipolar neuron is a neuron in which only one process, called a neurite, extends from the cell body. The neurite then branches to form dendritic and axonal processes. Most neurons in the central nervous systems of invertebrates, including insects, are unipolar. The cell bodies of invertebrate unipolar neurons are often located around the edges of the neuropil, in the so-called cell-body rind.
Most neurons in the central nervous systems of vertebrates, including mammals, are multipolar. In multipolar neurons, multiple processes extend from the cell body including dendrites and axons. Some neurons in the vertebrate brain have a unipolar morphology: a notable example is the unipolar brush cell, found in the cerebellum and granule region of the dorsal cochlear nucleus.
A third morphological class, bipolar neurons, extend just one axon and dendritic process from the cell body. Examples of bipolar neurons include most invertebrate sensory neurons and bipolar cells of the vertebrate retina.
Some vertebrate sensory neurons are classified as pseudo-unipolar. Pseudo-unipolar neurons initially develop as bipolar cells, but at some point the two processes that extend from the cell body fuse to form a single neurite. The axon then splits into two branches. Sensory neurons with cell bodies in the dorsal root ganglia of the vertebrate spinal cord are pseudo-unipolar: one branch projects to the periphery (to sensory receptors in the skin, joints, and muscle), the other to the spinal cord.


Thoracic spinal nerve 8

The thoracic spinal nerve 8 (T8) is a spinal nerve of the thoracic segment.
It originates from the spinal column from below the thoracic vertebra 8 (T8).


Tropic cues involved in growth cone guidance

The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.
Netrins.
Netrins are diffusible chemoattractive molecules that guide commissural axons across the midline; they are secreted by floor plate cells at ventral midline of the spinal cord. Netrins establish a gradient to direct commissural axons at a distance; Netrin-2 is expressed broadly in the ventral two thirds of the spinal cord, but not in the floor plate. Mice with netrin-1 loss-of-function exhibit severe disruption in commissural axon migration; this experiment established the importance of Netrin-1 in guidance decisions.
Netrin-1 gradient in "Xenopus laevis" ganglion cell can induce turning of retinal growth cones "in vitro" to steer axons out of the retina. Netrin (unc-6, "Caenorhabditis elegans" homologue) and its corresponding receptor DCC (Deleted in Colorectal Cancer) were initially identified as an attractive interaction. DCC, expressed by commissural axons, binds to netrin with high affinity; inhibiting netrin/DCC signaling interferes with the attractive turning of retinal growth cones.
Netrin-1 has also been shown to act as a chemorepellent "in vivo" for trochlear motor axons that migrate dorsally away from the floor plate. In netrin-1 deficient mice, trochlear axon projections are normal, suggesting the existence of other redundant guidance cues working in tandem with netrin-1 to repel trochlear axons.
Studies in "C. elegans" revealed a possible mechanism for netrin acting as a chemorepulsive agent (). Unc-5, a transmembrane protein, is required for dorsal migration of axons in nematodes; it was determined that unc-5 acts as a repulsive receptor for Netrin (unc-6). The switch between attractive and repulsive netrin signaling can be mediated by misexpression of unc-5 in commissural axons. Netrin-1/DCC binding induces DCC homodimerization leading to an attractive response; on the other hand, the chemorepellent response is triggered via netrin-1 binding to unc-5/DCC heterodimers.
Netrin repulsion can also be mediated by changes in cyclic nucleotide levels; netrin-1 induces a repulsive response when cAMP signaling is inhibited.
Cis interactions of netrin/DCC (attractive) and Slit/Robo (repulsive) in commissural axons silence both signaling cues; this illustrates how multiple tropic cues interact to guide the commissural axons to their targets.
Slits.
Repulsive cues play an important role in guiding growth cones to their appropriate target; roundabout (Robo) receptors and their ligand, Slit, are a well-studied example of repulsive guidance. Robo receptors were initially identified in "Drosophila melanogaster" using a forward genetic screen to search for molecules involved in midline crossing at the floor plate. Robo/Slit loss-of-function mutations result in axons crossing the midline multiple times, whereas gain-of-function results in little to no midline crossing; consequently this interaction was determined to be important in preventing non-commissural axons from crossing the midline and commissural axons from recrossing.
How the commissural axon regulates its response to Slit repulsion at the midline has been extensively studied in both "Drosophila" and vertebrates; in these two models the growth cone's response to Slit has been shown to be regulated through receptor trafficking and alternative splicing, respectively ().
Receptor trafficking is used extensively throughout growth cone migration; in "Drosophila" prior to crossing the midline these neurons express commissureless (comm), a protein involved in Robo receptor trafficking. Comm prevents Robo from reaching the cell membrane by targeting the receptor for the endosomal pathway; this allows the growth cone of the commissural axon to cross the midline by preventing Robo/Slit repulsive interactions. Comm expression turns off after the growth cone has crossed the midline; this permits Robo/Slit repulsion and prevents the growth cone from crossing the midline again.
Vertebrates, on the other hand, do not possess a comm homolog; instead they facilitate midline crossing through alternative splicing of Robo3 (aka.Rig-1). Robo3 has two isoforms, 3.1 and 3.2, and these isoforms interact with Robo1 and Robo2 (Robo1/2) through cis interactions at the leading edge of the growth cone. Before crossing the midline Robo3.1 inhibits Slit/Robo repulsive signaling, allowing the commissural axon to cross; after crossing the midline Robo 3.1 is replaced by Robo3.2 to facilitate the repulsive Slit/Robo signaling through cis interactions with Robo1/2.
Slit/Robo signaling is seen throughout the developing nervous system and is demonstrative of the importance of repulsive cues in growth cone migration; the aforementioned regulation of these repulsive barriers determines the path of the commissural axon.
Ephrins.
In the 1940s Roger Sperry was conducting experiments on newts and frogs to understand how axons are guided to their topographic locations; he did this by cutting the optic nerve and rotating the detached eye 180°. What he observed was that the animals behaved as if their visual world was back-to-front and upside-down when presented with a lure in front of them. He explained this behavior by the existence of two or more gradients "that spread across and through each other with their axes roughly perpendicular"; this became known as the chemoaffinity hypothesis. This subsequently lead to extensive research and the discovery of two repulsive factors, Ephrin-A5 and Ephrin-A2, by observing axon growth in retinal tissue culture on a striped carpet of anterior and posterior tectum membrane.
Ephrins are divided into 2 classes: Ephrin-As are bound to the membrane through GPI (glycosylphosphatidylinositol) linkage and Ephrin-Bs have a transmembrane domain and a short cytoplasmic domain; they interact with their respective receptors Eph-A and Eph-B which are members of the tyrosine kinase family. One unusual feature about Ephrins is their ability to bidirectionally signal (); they can participate in both forward (ligand to receptor) and reverse signaling (receptor to ligand). Eph/Ephrin binding induces conformational changes in the Ephrin transmembrane and cytoplasmic domains, activating the signaling pathway. Eph/Ephrin forward signaling regulates actin dynamics via small GTPases of the Rho family; reverse signaling occurs when the Ephrin-B cytoplasmic tail gets phosphorylated at tyrosine residues. Ephrin-B also contains a PDZ binding motif important in axon guidance regulation via G-protein signaling. Reverse signaling can also occur when Ephrin-A is activated by Eph-A3 binding; this is regulated by metalloprotease-dependent cleavage of Ephrin-A.
Eph/Ephrin bidirectional signaling is important for axon guidance and target selection; mapping of retinal axons along anterior-posterior axis in the visual system is regulated by Ephrin-A/Eph-A mediated repulsion. In the tectum, the transcription factor Engrailed creates an Ephrin-A concentration gradient along the anterior-posterior axis; this results in different signaling cues to the growth cones which also express graded levels of the receptor. The topographic location of retinal axons along dorsal-ventral axis requires both forward and reverse signaling by Ephrin-B/Eph-B gradient mediated attraction.
As described above for the visual system, Eph/Ephrin signaling plays an important role in topographic mapping in several other regions of the developing nervous system; the bidirectional signaling illustrates some of the complex regulatory mechanisms involved in growth cone guidance and target selection.
Semaphorins.
Semaphorins are a family of chemical signaling molecules involved in axonal targeting and guidance. Sema3 was the first vertebral Semaphorin discovered, and since then Semaphorins have been shown to elicit both attraction and repulsive responses in commissural axons; additionally, Semaphorins can function as a secreted or contact-dependent guidance cue ().
Semaphorins have also been shown to mediate other neuronal processes besides targeting such as: apoptosis, cell migration, axon pruning, synaptic transmission, and axonal transport. Semaphorins are the main ligands for the Neuropilin 1 (Npn1) receptor; this receptor is typically located in the medial and lateral portions of the lateral motor column during the early embryonic period of motor neuron development. Upon binding Semaphorins, the Npn1 receptor transmits signaling to adjacent surface molecules, known as Plexins; this is necessary because the Npn1 receptor lacks an intracellular domain. The intracellular signaling mediated through Semaphorins results in growth cone collapse, guidance, and turning; this intracellular signaling is transduced through Rho family GTPases, which act to remodel the cytoskeleton of the cell. In addition, several other cell surface molecules have been shown to interact with secreted Semaphorins. One example is the Ig cell-adhesion molecule (IgCAM) family; this family of adhesion molecules are suggested to interact with Semaphorins to fine tune their axonal projections and targeting. The multitude of molecules that complex with Semaphorins may be the result of the ubiquitous nature of Semaphorin expression in vertebrates.
During embryonic neurodevelopment, synapse elimination and axonal pruning are critical to ensure normal functioning of the central and peripheral nervous system. Studies have suggested that Sema3A/Neuropilin 2 (Npn2) interactions mediate synapse elimination and axonal pruning, as demonstrated by Sema3A/Npn2 loss-of-function studies in mice. The attractive cues mediated by Semaphorins are not well understood at the moment; however, protein kinase focal adhesion kinase (FAK) and MAP Kinase (MAPK) have been implicated in mediating downstream attractive signaling upon Semaphorin receptor stimulation.
Semaphorins also play a critical role in cranial nerve development; studies using mice deficient in Sema3A and Sema3F have resulted in abnormal cranial nerve extension and defasciculation, while Sema3F has been suggested to be required in order to establish projections of cranial nerves. Mice deficient in membrane bound Sema6A showed misprojection of corticothalamic fibers and axon projections from the hippocampus to olfactory bulb. Knocking out certain members of Semaphorins, such as Sema5A, resulted in embryonic lethality in mice and thus it has been difficult to elucidate the role of Sema5A in neurodevelopment. While the previous example suggested that Semaphorins may play pivotal roles in maintaining viable neurons, for the most part Semaphorin knockout animals display mild phenotypes.
Scientists thus hypothesize that there is considerable redundancy of Semaphorin family types. Future studies may focus on the implication of Semaphorins in neurologic diseases, and thus developing synthetic versions of Semaphorin receptor agonists/antagonists could be beneficial for both embryonic and adult neurologic dysfunction.


John Blackwell (musician)

John Blackwell Jr. (September 9, 1973 – July 4, 2017) was an American contemporary R&B, funk, jazz, fusion, and pop drummer, best known for his work with Prince. Later, he was a member of D'Angelo's backing band, The Vanguard.
Career.
Blackwell was born and raised in Columbia, South Carolina, and started playing drums at age 3. He learned from his father, John Blackwell Sr., a drummer himself, who played with Mary Wells, King Curtis, Joe Simon, J.J. Jackson, The Drifters, The Spinners, and others. Blackwell stated that he experienced synesthesia since he was a child, seeing colors for musical notes, and was identified as having perfect pitch while in high school.
As a teenager, Blackwell played in both his high-school jazz and marching bands. He began playing in jazz clubs at age 13. At 17, he landed his first professional gig backing jazz singer and bandleader Billy Eckstine. After high school, he attended Berklee College of Music and worked steadily in local Boston jazz clubs. He left Berklee in 1995 to play with the funk band Cameo, a gig which lasted for three years.
Blackwell moved to Los Angeles in 1998 to look for more drumming work, and got a job playing with Patti LaBelle for three years. He appeared on her 1998 album "Live! One Night Only", which won the Grammy Award for Best Traditional R&B Vocal Performance. Blackwell met Prince while performing with LaBelle in Minneapolis. Blackwell toured with Japanese singer Hikaru Utada, and then joined Prince's band, The New Power Generation, in September 2000.
Blackwell played with Prince on and off for 12 years, appearing on numerous releases, including the 2001 album, "The Rainbow Children", the 2003 "Live at the Aladdin Las Vegas" DVD, the 2003 instrumental album, "N.E.W.S", which was nominated for a Grammy Award for Best Pop Instrumental Album, and 2004's "Musicology". Blackwell performed with Justin Timberlake on his FutureSex/LoveShow tour. He has also played with Crystal Kay, P Diddy and Charlie Singleton. Blackwell played at the 2008 Buddy Rich Memorial Concert.
Blackwell played with Maze, featuring Frankie Beverly. He released his debut album in December 2009, titled "The John Blackwell Project". He has released two educational drumming DVDs: "John Blackwell - Technique, Grooving and Showmanship", and "John Blackwell". He joined the European leg of singer D'Angelo's The Second Coming Tour in 2015, as a member of his band, The Vanguard. He also toured as a member of bassist William "Bootsy" Collins' Bootsy's Rubber Band that year.
He had endorsements from Dixon Drums, Remo Drumheads, Regal Tip Drumsticks, and Turkish Cymbals. Previously, he endorsed Tama Drums, Yamaha Drums, Evans Drumheads, Sabian Cymbals, Zildjian Cymbals and Drumsticks, and Vater Drumsticks.
Blackwell joined Chinese musician Xu Wei's band for his tour named "At This Moment" in 2013. They performed in cities such as Beijing (May 17), Shanghai (July 13), Harbin (August 10), Hangzhou (August 24) and Shenzhen (September 7).
Death.
In July 2016 Blackwell announced that he had lost the use of his left arm and leg due to a brain tumor. On July 4, 2017, his wife announced his death. He was 43.


Pericallosal cistern

The pericallosal cistern is one of the subarachnoid cisterns. It lies along the top of the corpus callosum from the splenium to the genu. It then joins the cistern of lamina terminalis which connects it with the chiasmatic cistern.


Promestriene

Promestriene () (brand names Colpotrofin, Colpotrophine, Delipoderm), also known as estradiol 3-propyl 17β-methyl diether, is a synthetic estrogen which is used topically in a 1% cream formulation for the treatment of vaginal atrophy in women. It is the 3-propyl and 17β-methyl diether of estradiol and does not appear to convert into estradiol in the body. Promestriene is minimally absorbed and appears to have negligible systemic estrogenic effect. The drug has been described as a tropic agent and antiseborrheic. It has not been found to be effective in the treatment of pattern hair loss or other conditions of cutaneous androgenization. Promestriene was first introduced in France in 1974 and has been marketed in 34 countries worldwide. It has been used in millions of women.


Central melanocortin system

The central melanocortin system is defined anatomically as a collection of central nervous system circuits which include:
Mechanism of Action.
The melanocortin system is a critical regulator of energy balance, in both feeding behaviors and energy expenditure, as well as peripheral tissues such as skin and hair. This system is a principal nexus of body weight regulation through its role in appetite and energy expenditure via leptin, ghrelin and agouti-related protein. It receives inputs from hormones, nutrients and afferent neural inputs, and is unique in its composition of fibers which express both agonists and antagonists of melanocortin receptors. Much of what is known about brain control's of overall energy balance and fat storage stem from the discoveries about the hypothalamic melanocortin system and leptin.
Research into appetite-suppressants have further highlighted the role of the melanocortin system in weight homeostasis. Nicotine's appetite-suppressant effect appears to result from nicotine's stimulation of α3β4 nAChR receptors located in the POMC neurons in the arcuate nucleus and subsequently the melanocortin system via the melatocortin-4 receptors on second-order neurons in the paraventricular nucleus of the hypothalamus. Serotonin plays an essential role in mediating energy balance, including appetite suppression and weight reduction, by stimulation of the melanocortin-4 receptors, as was previously hypothesized, by a pathway to the brain stem via the hypothalamus, even though there are also peripheral pathways. Circadian rhythm signals also affect the melanocortin system, both directly with melatonin affecting POMC gene expression in the arcuate nucleas, and indirectly via the interdependence between serotonin and melatonin cycles. Selenoproteins indirectly regulate the melatocortin system via redox homeostasis.
Therapeutic Implications.
Due to the essential role of melanocortins in the regulation of body weight and appetite, they are a target of choice for anti-obesity drugs development, such as setmelanotide and lorcaserin, but also diabetes, cachexia and eating disorders such as anorexia. Other drugs target the serotonergic system to indirectly affect the melanocortin system for the treatment of obesity. However, it is important to note that this system also elicits effects on cardiovascular and sexual function.
Stimulation of the melanocortin-4 receptor causes a decrease in appetite and an increase in metabolism of fat and lean body mass, even in a relatively starved state. Conversely, damage to this receptor has been shown to result in morbid obesity, and is the most commonly known cause of monogenic morbid obesity. Mutation in an allele of the melanocortin-4 receptor causes 2-3% of childhood and adult obesity. Deficiencies and mutations in the melanocortin-4 receptors were also identified in the general population, thus rendering obsolete the distinction between rare monogenic obesity and common polygenic obesity.


Channel blocker

A channel blocker is the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce a physiological response in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.
Ion channels permit the selective passage of ions through cell membranes by utilizing proteins that function as pores, which allow for the passage of electrical charge in and out of the cell. These ion channels are most often gated, meaning they require a specific stimulus to cause the channel to open and close. These ion channel types regulate the flow of charged ions across the membrane and therefore mediate membrane potential of the cell.
Molecules that act as channel blockers are important in the field of pharmacology, as a large portion of drug design is the use of ion channel antagonists in regulating physiological response. The specificity of channel block molecules on certain channels makes it a valuable tool in the treatment of numerous disorders.
Background.
Ion channels.
To comprehend the mechanism of channel blockers, it is critical to understand the composition of ion channels. Their main function is to contribute to the resting membrane potential of a cell via the flow of ions through a cell membrane. To accomplish this task, ions must be able to cross the hydrophobic region of a lipid bilayer membrane, an unfavorable process. To assist in ion transport, ion channels form a hydrophilic pore through the membrane which allows for the usually unfavorable transfer of hydrophilic molecules. Various ion channels have varying mechanisms of function. They include:
Molecules that act as ion channel blockers can be used in relation to any of these various channels. For example, sodium channels, which are essential to the production of action potentials, are affected by many different toxins. Tetrodotoxin (TTX), a toxin found in pufferfish, completely blocks sodium ion transportation by blocking the selectivity filter region of the channel. Much of the structure of the pores of ion channels has been elucidated from studies that used toxins to inhibit channel function.
Identity.
Tools such as X-ray crystallography and electrophysiology have been essential in locating the binding sites of open channel block molecules. By studying the biological and chemical makeup of ion channels, researchers can determine the makeup of the molecules that bind to certain regions. X-ray crystallography provides a structural image of the channel and molecule in question. Determining the hydrophobicity of channel domains through hydrophobicity plots also provides clues to the chemical makeup of the molecule and why it binds to a certain region. For example, if a protein binds to a hydrophobic region of the channel (and therefore, has a transmembrane region), the molecule in question might be composed of the amino acids alanine, leucine, or phenylalanine, as they are all hydrophobic themselves. Electrophysiology is also an important tool in identifying channel structure, as analyzing the ionic factors that lead to channel activation can be critical to understanding the inhibiting actions of open channel block molecules.
Physiology.
Receptor antagonist.
Channel blockers are antagonists for the channels required to produce normal physiological function in cells. Many channels have binding spots for regulatory elements which can promote or repress normal function depending on the requirements within the cell and organism. The normal function of agonist binding is the generation of cellular changes leading to various downstream effects; these effects range from altering membrane potential to initiation of signaling cascades. Conversely, when open channel blockers bind to the cell they prevent the normal function of agonist binding. For example, voltage-gated channels open and close based on membrane potential and are critical in the generation of action potentials by their allowance of ions to flow down established gradients. However, open channels blockers can bind to these channels to prevent ions from flowing, thus inhibiting the initiation of an action potential.
Specificity of molecules.
Many different organic compounds can act as channel blockers despite channel specificity. Channels have evolved structures that, due to their membrane spanning regions, can discriminate between various ions or compounds. For example, some objects are too large for to fit into channels that are structurally specified to transport smaller objects, such as a potassium ion attempting to fit into a sodium channel. Conversely, some objects are too small to be properly stabilized by certain channel pores, such as a sodium ion attempting to pass through a potassium channel. In both cases, channel flux is not permitted. However, as long as a particular compound possesses adequate chemical affinity to a channel, that compound may be able to bind and block the channel pore. For example, TTX can bind and inactivate voltage-gated sodium channels, despite the fact that TTX is much larger and chemically different than sodium ions. Given the disparities in size and chemical properties between TTX and a sodium ion, this is an example of structure being used to block usually specific channels.
Kinetics.
A channel block can be induced by many different types of organic compounds as long as they can bind to some portion of the target channel's pore. The kinetics of channel blockers are primarily understood though their use as anesthetics. Local anesthetics work by inducing a phasic block state in the targeted neurons. Initially, open channel blockers do not effectively prevent action potentials, as few channels are blocked and the blocker itself can be released from the channel either quickly or slowly depending on its characteristics. However, phasic blocks occur as repeated depolarization increases blockers’ affinity for channels in the neuron. The combination of an increase in available channels and the change in channel conformation to increase blocker binding affinity are responsible for this action.
Clinical significance.
Therapeutic uses.
Various neurodegenerative diseases have been associated with excessive NMDA receptor activation meant to mediate calcium dependent neurotoxicity. Researchers have examined many different NMDA antagonists and their therapeutic efficacy, none of which have concluded to be both safe and effective. For years, researchers have been investigating the effects of an open channel block, memantine, as a treatment option for neurotoxicity. They hypothesized that the faster blocking and unblocking rates, and overall kinetics, of memantine could be the underlying reason for the clinical tolerance. As an uncompetitive antagonist, memantine should bring NMDA levels close to normal despite high glutamate concentration. Based on this information, researchers speculated that some day memantine could be used as an open channel block to prevent increasing glutamate levels associated with neurotoxicity with little to no side effects compared to other treatment options.
Alzheimer's disease.
Alzheimer's disease, a specific neurodegenerative disorder, is linked to glutaminergic neurotransmission interruptions that are believed to result in the staple cognitive symptoms of Alzheimer's. Researchers suggest that noncompetitive NMDA receptor agonists can be used to aid in the management of these symptoms without producing severe side effects. As one of the only drugs approved for Alzheimer's treatment, memantine has been shown to allow excitatory post synaptic currents to remain unaffected while decreasing the incidence and amplitude of inhibitory post-synatpic currents. Evidence supports the hypothesis that both the strong voltage dependency and fast kinetics of memantine may be responsible for the decreased side effects and cognitive progress.
Cystic fibrosis.
Cystic fibrosis is a progressive, genetic disease that is linked to CF transmembrane regulator (CFTR) dysfunction. Blockage of this channel by certain cytoplasmic, negatively-charged substances results in reduced chloride ion and bicarbonate anion transport, as well as reduced fluid and salt secretion. This results in a buildup of thick mucus, which is characteristic of cystic fibrosis.
Pharmacology.
Anesthetics.
Channel blockers are essential in the field of anesthetics. Sodium channel inhibitors are used as both antiepileptics and antiarrhythmics, as they can inhibit the hyper-excitable tissues in a patient. Introducing specific sodium channel blockers into a tissue allows for the preferential binding of the blocker to sodium channels, which results in an ultimate inhibition of the flow of sodium into the tissue. Over time, this mechanism leads to an overall decrease in tissue excitation. Prolonged hyperpolarization interrupts normal channel recovery and allows for constant inhibition, providing dynamic control of the anesthetics in a given setting.
Alzheimer's disease.
Excessive exposure to glutamate leads to neurotoxicity in patients with Alzheimer's disease. Specifically, over-activation of NMDA-type glutamate receptors have been linked to neural cell excitotoxicity and cell death. A potential solution to this is a decrease in NMDA receptor activity, without interfering so drastically as to cause clinical side effects.
In an attempt to prevent further neurodegeneration, researchers have used memantine, an open channel block, as a form of treatment. Thus far, the use of memantine in patients with Alzheimer's disease quickly results in clinical progress across many different symptoms. Memantine is thought to work effectively due to its ability to quickly modify its kinetics, which prevents buildup in the channel and allows normal synaptic transmission. Other channel blockers have been found to block all NMDA receptor activity, leading to adverse clinical side effects.
CFTR channel dysfunction.
Cystic Fibrosis transmembrane regulators (CFTRs) function in chloride ion, bicarbonate anion, and fluid transport. They are expressed primarily in apical membranes of epithelial cells in respiratory, pancreatic, gastrointestinal, and reproductive tissues. Abnormally-elevated CFTR function results in excessive fluid secretion. High-affinity CFTR inhibitors, such as CFTRinh-172 and GlyH-101, have been shown to be efficient in treatment of secretory diarrheas. Theoretically, CFTR channel blockers may also be useful as male contraceptives. CFTR channels mediate bicarbonate anion entry which is essential for sperm capacitation.
Various types of substances have been known to block CFTR chloride ion channels. Some of the best-known and studied substances include sulfonylureas, arylaminobenzenoates, and disulfonic stilbenes. These blockers are side-dependent as they enter the pore exclusively from the cytoplasmic side, voltage-dependent as hyperpolarized membrane potentials favor negatively-charged substance entry into the pore from the cytoplasmic side, and chloride ion concentration-dependent as high extracellular chloride ions electrostatically repel negatively-charged blockers back into the cytoplasm.
Types.
There are several different major classes of channel blockers, including:
The following types which act on ligand-gated ion channels (LGICs) via binding to their pore also exist:
Channel blockers are also known to act at AMPA receptors, Glycine receptors, Kainate receptors, P2X receptors and Zinc (Zn2+)-activated channels. The type of inhibition mediated by channel blockers may be referred to as noncompetitive or uncompetitive.


Dnipropetrovsk Oblast

Dnipropetrovsk Oblast (, "Dnipropetrovs'ka oblast" or Дніпропетровщина, "Dnipropetrovshchyna"), is an oblast (province) of central and eastern Ukraine, the most important industrial region of the country. It was created on February 27, 1932. Dnipropetrovsk Oblast has a population of about , approximately 80% of whom live centering on administrative center of Dnipro, Kryvyi Rih, Kamianske, Nikopol and Pavlohrad. The Dnipro River (Dnieper) runs through the oblast. In 2019, the Constitutional Court of Ukraine approved the change of the oblast's name to Sicheslav Oblast.
Geography.
The Dnipropetrovsk Oblast is located in southeastern Ukraine. The area of the oblast (31,974 km2) comprises about 5.3% of the total area of the country. Its longitude from north to south is 130 km, from east to west – 300 km. The oblast borders the Poltava and Kharkiv Oblasts on the north, the Donetsk Oblast on the east, the Zaporizhzhia and Kherson Oblasts on the south, and the Mykolayiv and Kirovohrad Oblasts on the west.
The Black Sea Lowland covers about half of the territory of the oblast. In Ternivka, a meteorite crater is located. It is in diameter and the age is estimated to be 280 ± 10 million years (Permian). The crater is not exposed at the surface. The Dnieper Upland contains a number of minerals including iron, manganese, granite, graphite, brown coal, kaolin etc. Kryvbas is an important economic region, specializing in iron ore mining and the steel industry. It is arguably the main iron ore region of Eastern Europe. Named after the city of Kryvyi Rih, the region occupies the southwestern part of the Dnipropetrovsk Oblast, as well as a small neighboring part of the Kirovohrad Oblast.
The region possesses major deposits of iron ore and some other metallurgical ores. To exploit them, several large mining companies were founded here in the middle of the 20th century. Most of them are located in Kryvyi Rih itself, which is the longest city in Europe.
Geology.
Much of the Dnipropetrovsk region is located within the boundaries of the Ukrainian Shield and only the northern regions and the extreme eastern part of the territory are confined to the south-eastern side of the Dnipro-Donets depression.
In the geological structure of the region, the breeds come from the archaea, the Proterozoic, the Paleozoic, the Mesozoic and the Cenozoic.
History.
In the 6th and 8th centuries, the first settlements of Slavs appeared on the banks of the Dnieper within the region. During the period of Kievan Rus' (9-12 centuries AD) the Dnieper River was one of the main trade routes of medieval Eastern Europe called "From the Varangians to the Greeks", which connected the Baltic countries with the Crimea and the capital of Byzantium, Constantinople. The Dnieper also served as a major route for transporting the army of Kyiv princes on their way to the Byzantine coastal cities in the early 9th and late 9th centuries.
At the beginning of the 15th century, Tatar tribes inhabiting the right bank of the Dnieper were driven away by the Grand Duchy of Lithuania. However, by the mid-15th century, the Nogai (who lived north of the Sea of Azov) and the Crimean Khanate invaded these lands. The Grand Duchy of Lithuania and the Crimean Khanate agreed to a border along the Dnieper, and farther east along the Samara River, i.e. through what is today the city of Dnipro. It was in this time that there appeared a new force, the Cossacks, armed freemen not subject to any feudal lord who were to soon dominate the region. They later became known as Zaporozhian Cossacks, from Zaporizhzhia, the lands south of Naddniprianshchyna, which translates as "the Land Beyond the Weirs [Rapids]"). This was a period of raids and fighting causing considerable devastation and depopulation in that area; the area became known as the 'Wilderness'.
In 1635, the Polish Government built the Kodak fortress above the Dnieper Rapids at "Kodaky", partly as a result of rivalry in the region between Poland, Turkey and the Crimean Khanate, and partly to maintain control over Cossack activity (i.e. to suppress the Cossack raiders and to prevent peasants moving out of the area). On the night of 3 or 4 August 1635, the Cossacks of Ivan Sulyma captured the fort by surprise, burning it down and butchering the garrison of about 200 West European mercenaries under Jean Marion. The fort was rebuilt by French engineer Guillaume Le Vasseur de Beauplan for the Polish Government in 1638, and had a mercenary garrison. "Kodak" was captured by Zaporozhian Cossacks on 1 October 1648, and was garrisoned by the Cossacks until its demolition in accordance with the Treaty of the Pruth in 1711.
Under the Treaty of Pereyaslav of 1654, the territory became part of the Russian Empire. In 1774 Prince Grigori Potemkin was appointed governor of Novorossiysk Governorate, and after the destruction of the Zaporozhian Sich, he started founding cities in the region and encouraging foreign settlers. The city of "Yekaterinoslav" was founded in 1776, not in the current location, but at the confluence of the River Samara with the River Kil'chen' at Loshakivka, north of the Dnieper. On May 8, 1775, after the end of the Russian-Turkish War, Russian authorities opened a postal station and track which linked Kremenchuk, Kinburn foreland and Ochakiv, all locations of the Imperial Russian Army.
In December 1796, Paul I reestablished the Novorossiysk Governorate, mostly with land from the former Yekaterinoslav Viceroyalty. In 1802, this province was divided into the Nikolayev Governorate (known as the Kherson Governorate from 1803), Yekaterinoslav Governorate, and the Taurida Governorate. Its capital was the city of Yekaterinoslav (modern Dnipro) created in 1802 out the Yekaterinoslav Vice-regency. It was located within the former lands of Zaporizhian Sich. The government bordered to the north with the Kharkov Governorate and Poltava Governorate, to the west and southwest with the Kherson Governorate, to the south with the Taurida Governorate and Sea of Azov, and to the east with Don Host Oblast.
Olexander Paul discovered and initiated iron ore investigation and production, and this in turn caused the formation of a mining district. In 1874 Alexander II initiated the founding project of a railway, running . This enabled transportation directly to the nearest factories and greatly sped up the development of the region.
On 1 August 1925, the Yekaterinoslav Governorate administration was discontinued, and in 1926 the city of Yekterinoslav was renamed Dnipropetrovsk in honor of communist leader Grigory Petrovsky. Before the introduction of oblasts in 1932, Ukraine comprised 40 okrugs, which had replaced the former Russian Imperial guberniya (governorate) subdivisions. In 1932 the territory of the Ukrainian SSR was re-established based on oblasts. The first oblasts were Vinnytsia Oblast, Kyiv Oblast, Odessa Oblast, Kharkiv Oblast, and Dnipropetrovsk Oblast. Soon after that in the summer of 1932 Donetsk Oblast was formed out of eastern parts of Kharkiv and Dnipropetrovsk.
During the Holodomor more than 200 collective farms in Dnipropetrovsk Oblast were put on "Blackboards" which was a complete blockade of trade and food aid to villages under performing in grain procurement quotas; a number representing more than half of all such "Blackboards" throughout all of Ukraine.
During the 1991 referendum, 90.36% of votes in Dnipropetrovsk Oblast were in favor of the Declaration of Independence of Ukraine. A survey conducted in December 2014 by the Kyiv International Institute of Sociology found 2.2% of the oblast's population supported their region joining Russia, 89.9% did not support the idea, and the rest were undecided or did not respond.
The city of Dnipropetrovsk was renamed Dnipro in May 2016 as part of the decommunization laws enacted a year earlier. Dnipropetrovsk Oblast was not renamed because it is mentioned as such in the Constitution of Ukraine, and the oblast can only be renamed by a constitutional amendment. In April 2018 a group of over a hundred deputies formally initiated a proposal in the Ukrainian Parliament to change the name to Sicheslav Oblast; in February 2019, the Verkhovna Rada voted to officially amend the Constitution thus granting state sanction to the name change. Later that year the Constitutional Court officially approved the change. The oblast's administrative centre and largest city, Dnipro, had the unofficial name "Sicheslav" in 1918–21 during the Ukrainian War of Independence, commemorating the Zaporizhian Sich.
Administrative subdivisions.
The following data incorporates the number of each type of administrative divisions of the Dnipropetrovsk Oblast:
The local administration of the oblast is controlled by the Dnipropetrovsk Oblast Rada. The governor of the oblast is the Dnipropetrovsk Oblast Rada speaker, appointed by the President of Ukraine.
Demographics.
Its population in 2004 was 3,493,062, which constituted 5.3% of the overall Ukrainian population.
At the 2001 census, the ethnic groups within the Dnipropetrovsk Oblast were:
the groups by native language:
Religion.
A Pew survey of Dnipropetrovsk residents' religious self-identification showed the following distribution of affiliations: Ukrainian Orthodox Church (Moscow Patriarchate) 47.5%, Ukrainian Orthodox Church of the Kyivan Patriarchate 10.7%, Roman Catholic 1.3%, Ukrainian Autocephalous Orthodox Church 0.8%, Protestantism 32.3%.
Dnipropetrovsk has one of the most balanced percentage of religious people in the nation mainly due to large number of ethnic groups. The Jewish community is centered in the Dnipro (Golden Rose Synagogue) and Kryvyi Rih area, and emerged during a wave of Jewish immigration.
Cities and towns.
There are 20 cities and towns in Dnipro. Major population centers today result from historical factors — with the advent of the iron development took place predominantly along the Kryvyi Rih, Dnipro located on River Dnieper. Kryvyi Rih is the base of a large metropolitan area.
Ranked by population, the state's 12 largest municipalities are:
Transport.
There are eight over-Dnieper bridges and dozens of grade-separated intersections. Several new intersections are under construction. European route E105 cross Left-bank Dnipro from North to South. Highway M04 (Ukraine) and Highway M18 (Ukraine) cross River Dnieper and Dnipro from West to East, entering Kryvyi Rih. Overall, roads are in poor technical condition and maintained inadequately.
Near-Dnipro Railway (NDZ), headquartered in Dnipro, is a component part of the Ukrzaliznytsia (UZ) company. NDR's route map includes all the railroads in the Dnipropetrovsk, Zaporizhya, Kharkiv, Kherson and Crimea oblasts (provinces of Ukraine).
As of 2008, NDR's rail system included 3,275 km (2,035 mi) of track, of which 93,3% were electrified. The PDR consists of five sections (directions), the Dnipropetrovsk, Zaporizhya, Kryvyi Rih, and Crimea directions. There are 244 railway stations in the NDR system. More than a dozen "elektrichka" stops are located within the city allowing residents of different neighborhoods to use the suburban trains.
The cities of Dnipro and Kryvyi Rih are served by a local sales-tax-funded bus, tram, metro and trolleybus systems.
Dnipro International Airport is the only international airport in the state and serves as one of the hubs for Dniproavia. The airport has non-stop service to over 20 destinations throughout Ukraine, Russia, and Turkey, as well as to Vienna and Tel Aviv. Kryvyi Rih International Airport provides limited commercial air service.
Environment.
The oblast is situated in the steppe region. Forests in the oblast occupy about 3.9% of the oblast's total territory. The average temperature in the winter balances from −3 to −5 °C and in the summer from 22 to 24 °C. The average annual rainfall is 400–490 mm. During the summer, Dnipropetrovsk oblast is very warm (average day temperature in July is 24 to 28 °C (75 to 82 °F), even hot sometimes 34 to 38 °C (90 to 97 °F). Temperatures as high as 36 °C (97 °F) have been recorded in May. Winter is not so cold (average day temperature in January is −3 to 0 °C (25 to 32 °F), but when there is no snow and the wind blows hard, it feels extremely cold. A mix of snow and rain happens usually in December.
The tender climate, mineral sources, and the curative mud allow opportunities for rest and cure within the region. Here there are 21 health-centers and medicated pensions, 10 rest homes, recreation departments and rest camps for children.
The Dnipropetrovsk Oblast has splendid flora and fauna. Here, there are more than 1700 kinds of vegetation, 7500 kinds of animals (including elk, wild boar, dappled deer, roe, hare, fox, wolf, etc.) There are also 114 park and nature objects, including 15 state reserves; 3 nature memorials, 24 local parks; 7 landscape parks; 3 park tracts, which altogether make up approximately 260 square kilometres.
217 rivers flow within the area, including 55 rivers which are longer than 25 km, the major one being the Dnieper, which crosses through the center of the oblast. Also flowing through the region are three major reservoirs, the Kamianske, Dnieper and Kakhovka, and the Dnieper-Kryvyi Rih Canal.
Economy.
The Dnipropetrovsk Oblast has a high industry potential. There are 712 basic industrial organizations, including 20 different types of economic activity with about 473,4 thousand workers. The area also produces about 16.9% of the total industry production of Ukraine. This places the Dnipropetrovsk Oblast second in Ukraine (after the neighbouring Donetsk Oblast).
Dnipro is a major industrial centre of Ukraine. It has several facilities devoted to heavy industry that produce a wide range of products, including cast-iron, rolled metal, pipes, machinery, different mining combines, agricultural equipment, tractors, trolleybuses, refrigerators, different chemicals and many others. The most famous and the oldest (founded in the 19th century) is the Metallurgical Plant named after Petrovsky. The city also has big food processing and light industry factories. Many sewing and dress-making factories work for France, Canada, Germany and Great Britain , using the most advanced technologies, materials and design. Dnipro has also dominated in the aerospace industry since the 1950s; construction department Yuzhnoye Design Bureau and Yuzhmash are well known to the specialists all over the world.
Yuzhmash is a manufacturer of space rockets, agricultural equipment, buses, trolley buses, trams, wind turbines, and satellites that was inherited from the Soviet Union. It is a large state-owned company located in Dnipro.
Dniproavia, an airline, has its head office on the grounds of Dnipropetrovsk International Airport.
The region possesses major deposits of iron ore and some other metallurgical ores. To exploit them, several large mining companies were founded here in the middle of the 20th century. Most of them are located in Kryvyi Rih itself, which is the longest city in Europe. Steel companies of the region (except Mittal Steel-owned Kryvorizhstal) are controlled by either the Privat Group or the SCM. From the 1990s until 2004, these once united and state-owned industries went through a hard and scandal-ridden process of privatization. Being a business oligarch entity, Privat Group controls some prominent Ukrainian media, maintains close relations with politicians and sponsors professional sports. Key businesses of the group (including the Privatbank itself) are based in Dnipropetrovsk Oblast, which is regarded as its "homeland". Group's founding owners are natives of Dnipropetrovsk and made their entire career there.
ArcelorMittal Kryvyi Rih, owned by ArcelorMittal since 2005 is the largest private company by revenue in Ukraine, producing over 7 million tonnes of crude steel, and mined over 17 million tonnes of iron ore. As of 2011, the company employed about 37,000 people. 4 Iron Ore Enrichment Works of Metinvest are a large contributors to the UA's balance of payments. The third giant – Evraz mining company.
Education.
Colleges and universities.
Dnipropetrovsk has several colleges and universities:
Sport.
Region houses the Ukrainian Premier League football club, FC Dnipro. This club, commonly seen as representing the city at large, holds a record for being the only Soviet team to win the USSR Federation Cup twice; since independence they have gone on to win the Ukrainian Championship once and the Ukrainian League Cup three times. Kryvyi Rih was home to the football team Kryvbas Kryvyi Rih. FC Hirnyk Kryvyi Rih is a club based in Kryvyi Rih. The club currently competes in the Ukrainian First League. It is part of the Sports Club Hirnyk which combines several other sections. The club's owner is the Kryvyi Rih Iron Ore Combine (KZRK), the biggest subterranean mining public company in Ukraine.
SC Kryvbas is a professional basketball club. Achievements of the team are winning the Ukrainian Basketball League in 2009, and winning the Higher League in 2003 and 2004. Since 2010 the team is active in the Ukrainian Basketball SuperLeague.
Recently built Dnipro-Arena has a capacity of 31,003 people. The Dnipro-Arena hosted the 2010 FIFA World Cup qualification game between Ukraine and England on 10 October 2009. The Dnipro Arena was initially chosen as one of the Ukrainian venues for their joint Euro 2012 bid with Poland. However it was dropped from the list in May 2009 as the capacity fell short of the minimum 33,000 seats required by UEFA.
Dnipropetrovsk has a regional federation within Ukrainian bandy and Rink Bandy Federation.
Culture.
Historically, Dnieper Ukraine comprised territory that roughly corresponded to the area of Ukraine within the expanding Russian Empire. Ukrainians sometimes call it Great Ukraine (Velyka Ukrayina). Historically, this region is tightly entwined with the history of Ukraine and is considered as the heart of the country.
Ukrainian (Middle Dnieprian dialect, 67,0%) and Russian (31,9%) language are both equally used officially, with Russian being more common in cities, while Ukrainian is the dominant language in rural communities. These details result in a significant difference across different survey results, as even a small restating of a question switches responses of a significant group of people. The speaking of Surzhyk instead of Russian or Ukrainian is wide and viewed negatively by nationalist language activists. Because it is neither the one nor the other, they regard Surzhyk as a threat to the uniqueness of Ukrainian culture.
Petrykivsky Painting originates from Petrykivka village. The distinctive features of this handicraft are the patterns, unusual technique and white background. It was included to the UNESCO Representative List of the Intangible Cultural Heritage of Humanity.
Landmarks.
The following historical-cultural sites were nominated to the Seven Wonders of Ukraine.
Symbols.
A Cossack with a musket was an emblem of the Zaporizhian Host and later the state emblem of the Hetmanate and the Ukrainian State. The origin of the emblem is uncertain, while its first records date back to 1592. On the initiative of Pyotr Rumyantsev the emblem was phased out and replaced by the Russian double-headed eagle in 1767.
A Cossack with a rifle was restored by the Hetman of Ukraine Pavlo Skoropadsky in 1918. However, later the emblem disappeared again until in 2005 it reappeared on the proposed Great Seal of Ukraine. In 2002 was adopted flag and identical coat of arms of Oblast, which consists of cossack with musket and nine yellow eight-pointed stars. Stars represent coat of arms of Yekaterinoslav Governorate which also consisted of imperial monogram of Catherine the Great.


Epiphany term

Epiphany term is the second academic term at Durham University, falling between Michaelmas term and Easter term, as in the Christian Feast of the Epiphany, held in January.
The term runs from January until March, equivalent to the Spring term at many British universities, Hilary term at Dublin and Oxford, and Lent term at Cambridge, Canterbury Christ Church, Lancaster, Liverpool, LSE and Swansea.
Historically, the name has been in use at Durham since the university's opening in 1833, and was also used at Newcastle University (formerly King's College of Durham University) until 2004. It was also used at Durham's overseas affiliated colleges: Codrington College, Barbados, and Fourah Bay College, Sierra Leone, and is used (as of July 2018) by Sierra Leone Law School.
In the United States, the name was in use in the late 19th century at Hobart College, NY, and at Divinity School of the Protestant Episcopal Church, PA, and for a period after 1913 at .
The name remains in use (interchangeably with "Spring term") at the General Theological Seminary, NY.