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Peripherin

Peripherin is a type III intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks (networks formed from peripherin protein dimers), but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene. Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.

History
Peripherin, first named such in 1984, was also known as 57 kDa neuronal intermediate filament prior to 1990. In 1987, a second distinct peripherally located retinal rod protein was also given the name peripherin. To distinguish between the two, this second protein is referred to peripherin 2 or peripherin/RDS (retinal degeneration slow) for its location and role in retinal disease.

Structure and properties
Peripherin was discovered as being the major intermediate filament in neuroblastoma cell lines and in rat pheochromocytoma cells. It is classified by gene structure and coding sequence as a type III intermediate filament protein because of its homology with vimentin, glial fibrillary acidic protein, and desmin. All intermediate filament proteins share a common secondary structure consisting of three main domains, the most conserved of which is the central α-helical rod domain. This central coil is capped by non-helical head (N-terminal) and tail (C-terminal) domains. The α-helical rod domain contains repeating segments of hydrophobic amino acids, such that the first and fourth residues of every set of seven amino acids are usually nonpolar. This specific structure enables two intermediate filament polypeptides to coil together and create a "hydrophobic seal". The rod also contains specific placement of alternating acidic and basic residues, many of which are spaced 4 amino acids apart. This spacing is optimal for the formation of ionic salt bridges, which serve to stabilize the α-helical rod through intrachain interactions. A switch from intrachain salt bridges to interchain ionic associations may assist in intermediate filament assembly by utilizing electrostatic interactions to stabilize coiled-coil dimers. The head and tail regions of intermediate filament proteins vary in length and amino acid composition, with greater variations in length occurring in the tail regions.

Peripherin, unlike keratin IFs, can self-assemble and exist as homopolymers (see polymer). They can also heteropolymerize, or co-assemble, with other type III proteins or the light neurofilament subunit (NF-L) to form intermediate filament networks. Type III proteins like peripherin can exist in different states within a cell. These states include nonfilamentous particles which combine to firm short IFs, or squiggles. These squiggles come together to form long IFs that make up cytoskeletal networks. Studies of network assembly in spreading fibroblasts and differentiating nerve cells show that particles move along microtubules in a kinesin and dynein-dependent manner, and as spreading continues, the particles polymerize into intermediate filaments.

In addition to the main species of peripherin, 57 kDa, two other forms have been identified in mice: Per 61 and Per 56. These two alternatives are both made by alternative splicing. Per 61 is created by introducing a 32 amino acid insertion within coil 2b of the α-helical rod domain of peripherin. Per 56 is made by a receptor on exon 9 of the peripherin gene transcript which induces a frameshift and replacement of a 21 amino acid sequence in the C-terminal found on the dominant 57 form with a new 8 amino acid sequence. The functions of these two alternative forms of peripherin are unknown. Per 57 and 56 are normally co-expressed, whereas Per 61 is not found in normal peripherin expression in adult motor neurons.

Tissue distribution
Peripherin is widely expressed in the cell body and axons of neurons in the peripheral nervous system. These include small-sized root ganglion neurons, lower motor neurons, sensory and motor neurons of the cranial nerves, and autonomic neurons in ganglia and the enteric nervous system. It is also expressed in the central nervous system in a small set of brainstem and spinal cord neurons that have projections toward peripheral structures. Some of these structures include the hypothalamic magnocellular nuclei, pontine cholinergic nuclei, some cerebellar nuclei, and scattered neurons in the cerebral cortex. They can also be found in the ventral horn neurons and in the cholinergic laterodorsal tegmentum (LDT) and pedunculopontine tegmentum (PPT) nuclei.

A comparison of peripherin expression in the posterior and lateral hypothalamus in mice showed a sixty-fold higher expression in the posterior hypothalamus. This higher expression is due to the presence of peripherin in the tuberomammillary neurons of the mouse posterior hypothalamus.

Function
The diverse properties of intermediate filaments, compared with the conserved microtubule and actin filament proteins, could be responsible for the distinguishing molecular shapes of different cell types. In nerve cells, for example, the expressions of different types of IFs relates to the change in shape during development. Early stages of development in neurons is marked by the outgrowth of neurites and axons contributing to the cells asymmetric shape. During these transitions in cell shape, only homopolymer type III intermediate filaments, such as those with peripherin, are made. As the nerve cell matures, these type III IFs are replaced by more complex type IV neurofilaments expanding the diameter of axons in order to attain normal velocities of action potentials.

The exact function of peripherin is unknown. Expression of peripherin in development is greatest during the axonal growth phase and decreases postnatally, which suggests a role in neurite elongation and axonal guidance during development. Expression is also increased after axonal injury, such as peripheral axotomy in motor neurons and dorsal root ganglia. This upregulation implies that peripherin may also play a role in axon regeneration. However, experiments using peripherin depleted PC12 cells and peripherin knockout mice provide proof that the majority of neurons have no requirement of peripherin for axonal guidance and regrowth. PC12 cells lacking peripherin showed no defects in neurite outgrowth and peripherin knockout mice develop normally with no anatomical abnormalities or different phenotypes. In these experiments, peripherin deficiency did produce an upregulation of α-internexin, indicating the possibility that this type IV intermediate filament makes up for the loss of peripherin. Future studies of double knockout mice for both the peripherin and α-internexin genes might address this theory. However, while most peripherin knockout mice displayed normal neuron growth, its absence did affect development of a subset of unmyelinated sensory axons. In such mice, there was a "34% reduction in the number of L5 unmyelinated sensory fibers that correlated with a decreased binding of the lectin IB4."

Gene (PRPH)
The complete sequence of the human (GenBank L14565), rat (GenBank M26232) and mouse (EMBL X59840) peripherin genes (PRPH) have been reported and complementary DNAs (cDNA) thus far described are those for rat, mouse and Xenopus peripherin. The use of a mouse cDNA probe during the in situ hybridization procedure allowed for the localization of the PRPH gene to the E-F region of mouse chromosome 15 and the q12-q13 region of human chromosome 12.

The overall structure of the peripherin gene is nine exons separated by eight introns. This configuration is conserved among the three known mammalian species with known coding for peripherin, namely human, rat and mouse. The nucleotide sequences of human and rat exons were 90% identical and produced a predicted protein that differed at only 18 of 475 amino acid residues. Comparison of introns 1 and 2 also yielded high homology of conserved segments. The 5' flanking regions and regulatory sequences were also very similar and a nerve growth factor negative regulatory element, a Hox protein (See Hox gene) binding site, and a heat shock element were found in all known peripherin genes.

Regulatory mechanisms
Nerve growth factor (NGF) plays the major role in the regulation of peripherin. It is both a transcriptional inducer and post-translational regulator of peripherin expression in PC12 and neuroblastoma cells. The mechanism of NGF-induced activation occurs through 5' flanking elements and intragenic sequences involving the TATA box and other upstream elements as well as depression at a negative element. The specific signals regulating peripherin expression in vivo are unknown. The peripherin gene is transcriptionally activated in both small and large sized sensory neurons of the dorsal root ganglion at about day E10, and mRNA is present in these cells after postnatal day 2 and throughout adulthood. Post transcriptional mechanisms reduce detectable peripherin to only the small sized cells; however, crushing of the peripheral processes in dorsal root ganglion neurons lead to mRNA and detectable peripherin in the large sized cells.

The proinflammatory cytokines, interleukin-6 and leukemia inhibitory factor, can also induce peripherin expression through the JAK-STAT signaling pathway. This specific upregulation is linked to neuronal regeneration.

Potential role in the pathogenesis of amyotrophic lateral sclerosis
Protein and neurofilamentous aggregates are characteristic of patients with amyotrophic lateral sclerosis, a progressive, fatal neurodegenerative disease. Spheroids, specifically, which are protein aggregates of neuronal intermediate filaments, have been found in patients with amyotrophic lateral sclerosis. Peripherin has been found in such spheroids in conjunction with other neurofilaments in other neuronal diseases, thus suggesting that peripherin may play a role in the pathogenesis of amyotrophic lateral sclerosis.

Alternative splicing
An alternatively spliced mouse peripherin variant was identified that includes intron 4, a region that is spliced out of the abundant peripherin forms. Because of the change in reading frame, this variant produces a larger form of peripherin (Per61). In human peripherin, the inclusion of introns 3 and 4, regions that are similarly spliced out of the abundant peripherin protein forms, results in the generation of a truncated peripherin protein (Per28). In both cases, an antibody specific to a peptide coded by the intron regions stained the filamentous inclusions of in tissues affected by amyotrophic lateral sclerosis. These studies suggest that such alternative splicing could play a role in the disease and lend themselves to further investigation.

Mutations
Experiments examining peripherin overexpression in mice have suggested that PRPH mutations play a role in the pathogenesis of amyotrophic lateral sclerosis, with more recent studies investigating the prevalence of such mutations in humans. Though many polymorphic variants of PRPH exist, two variants of PRPH were seen uniquely in patients with ALS, both of which consisted of a frameshift mutation. In the first variant, a single base pair deletion in exon 1 of PRPH was predictive of a peripherin species truncated to 85 amino acids. This truncation negatively impacted the ability of the neurofilament network to assemble, thus suggesting that mutations in PRPH may play a role in at least a small percentage of human cases of amyotrophic lateral sclerosis.

The second variant consisted of an amino acid substitution from aspartate to tyrosine as a result of a single point mutation in exon 1. This was also shown to adversely affect the assembly of the neurofilament network. The PRPH mutations observed in amyotrophic lateral sclerosis cause a change in the 3D structure of the protein. Consequently, the mutant peripherin forms aggregates instead of the filamentous network that it usually forms.

Other clinical significance
Peripherin may be involved in the pathology of insulin-dependent diabetes mellitus (or diabetes mellitus type 1) in animals; however, no direct linkage has been found in human patients. In a nonobese diabetic mouse model, peripherin has been found as a known autoantigen (See antigen). B cell clones reactive to peripherin have also been found in early stages of the disease. Since peripherin is expressed in both the peripheral nervous system and, in young animals, by islet beta cells, it is possible that the destruction of both peripheral nervous system elements and islet β-cells in insulin-dependent diabetes mellitus is due to the immune response to autoreactive peripherin.

Peripherin can also play a role in the definitive diagnosis of Hirschsprung disease. Patients suspected of having the disease undergo rectal biopsy to look for the presence or absence of ganglion cells. However, the identification of these cells can be very difficult, especially in newborns where immature ganglion cells are easily confused with endothelial, mesenchyme and inflammatory cells. To aid in identification, a protocol utilizing peripherin and S-100 immunohistochemistry staining was developed to assist in the recognition of ganglion cells in rectal biopsies.

Potential applications
Possible involvement of intermediate filaments such as peripherin in neurodegenerative diseases is currently being investigated. Interactions between intermediate filaments and other proteins are also being pursued. Peripherin has been shown to associate with protein kinase Cε, inducing its aggregation and leading to increased apoptosis. It may be possible to regulate this aggregation and apoptosis using siRNAs and protein kinase Cε. Pinpointing the source and possible resolution of protein aggregates is a promising direction for potential therapeutics.

title: Peripherin


text:
GFAP

GFAP may refer to:
 * Glial fibrillary acidic protein
 * General Framework Agreement for Peace in Bosnia and Herzegovina, also known as the Dayton Agreement

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: GFAP


text:
Glial fibrillary acidic protein

Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the GFAP gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astrocytes and ependymal cells during development. GFAP has also been found to be expressed in glomeruli and peritubular fibroblasts taken from rat kidneys, Leydig cells of the testis in both hamsters and humans, human keratinocytes, human osteocytes and chondrocytes and stellate cells of the pancreas and liver in rats.

GFAP is closely related to the other three non-epithelial type III IF family members, vimentin, desmin and peripherin, which are all involved in the structure and function of the cell's cytoskeleton. GFAP is thought to help to maintain astrocyte mechanical strength as well as the shape of cells, but its exact function remains poorly understood, despite the number of studies using it as a cell marker. The protein was named and first isolated and characterized by Lawrence F. Eng in 1969. In humans, it is located on the long arm of chromosome 17.

Structure
Type III intermediate filaments contain three domains, named the head, rod and tail domains. The specific DNA sequence for the rod domain may differ between different type III intermediate filaments, but the structure of the protein is highly conserved. This rod domain coils around that of another filament to form a dimer, with the N-terminal and C-terminal of each filament aligned. Type III filaments such as GFAP are capable of forming both homodimers and heterodimers; GFAP can polymerize with other type III proteins. GFAP and other type III IF proteins cannot assemble with keratins, the type I and II intermediate filaments: in cells that express both proteins, two separate intermediate filament networks form, which can allow for specialization and increased variability.

To form networks, the initial GFAP dimers combine to make staggered tetramers, which are the basic subunits of an intermediate filament. Since rod domains alone in vitro do not form filaments, the non-helical head and tail domains are necessary for filament formation. The head and tail regions have greater variability of sequence and structure. In spite of this increased variability, the head of GFAP contains two conserved arginines and an aromatic residue that have been shown to be required for proper assembly.

Function in the central nervous system
GFAP is expressed in the central nervous system in astrocyte cells, and the concentration of GFAP differs between different regions in the CNS, where the highest levels are found in medulla oblongata, cervical spinal cord and hippocampus. It is involved in many important CNS processes, including cell communication and the functioning of the blood brain barrier.

GFAP has been shown to play a role in mitosis by adjusting the filament network present in the cell. During mitosis, there is an increase in the amount of phosphorylated GFAP, and a movement of this modified protein to the cleavage furrow. There are different sets of kinases at work; cdc2 kinase acts only at the G2 phase transition, while other GFAP kinases are active at the cleavage furrow alone. This specificity of location allows for precise regulation of GFAP distribution to the daughter cells. Studies have also shown that GFAP knockout mice undergo multiple degenerative processes including abnormal myelination, white matter structure deterioration, and functional/structural impairment of the blood–brain barrier. These data suggest that GFAP is necessary for many critical roles in the CNS.

GFAP is proposed to play a role in astrocyte-neuron interactions as well as cell-cell communication. In vitro, using antisense RNA, astrocytes lacking GFAP do not form the extensions usually present with neurons. Studies have also shown that Purkinje cells in GFAP knockout mice do not exhibit normal structure, and these mice demonstrate deficits in conditioning experiments such as the eye-blink task. Biochemical studies of GFAP have shown MgCl2 and/or calcium/calmodulin dependent phosphorylation at various serine or threonine residues by PKC and PKA which are two kinases that are important for the cytoplasmic transduction of signals. These data highlight the importance of GFAP for cell-cell communication.

GFAP has also been shown to be important in repair after CNS injury. More specifically for its role in the formation of glial scars in a multitude of locations throughout the CNS including the eye and brain.

Autoimmune GFAP astrocytopathy
In 2016 a CNS inflammatory disorder associated with anti-GFAP antibodies was described. Patients with autoimmune GFAP astrocytopathy developed meningoencephalomyelitis with inflammation of the meninges, the brain parenchyma, and the spinal cord. About one third of cases were associated with various cancers and many also expressed other CNS autoantibodies.

Meningoencephalitis is the predominant clinical presentation of autoimmune GFAP astrocytopathy in published case series. It also can appear associated with encephalomyelitis and parkinsonism.

Disease states
There are multiple disorders associated with improper GFAP regulation, and injury can cause glial cells to react in detrimental ways. Glial scarring is a consequence of several neurodegenerative conditions, as well as injury that severs neural material. The scar is formed by astrocytes interacting with fibrous tissue to re-establish the glial margins around the central injury core and is partially caused by up-regulation of GFAP.

Another condition directly related to GFAP is Alexander disease, a rare genetic disorder. Its symptoms include mental and physical retardation, dementia, enlargement of the brain and head, spasticity (stiffness of arms and/or legs), and seizures. The cellular mechanism of the disease is the presence of cytoplasmic accumulations containing GFAP and heat shock proteins, known as Rosenthal fibers. Mutations in the coding region of GFAP have been shown to contribute to the accumulation of Rosenthal fibers. Some of these mutations have been proposed to be detrimental to cytoskeleton formation as well as an increase in caspase 3 activity, which would lead to increased apoptosis of cells with these mutations. GFAP therefore plays an important role in the pathogenesis of Alexander disease.

Notably, the expression of some GFAP isoforms have been reported to decrease in response to acute infection or neurodegeneration. Additionally, reduction in GFAP expression has also been reported in Wernicke's encephalopathy. The HIV-1 viral envelope glycoprotein gp120 can directly inhibit the phosphorylation of GFAP and GFAP levels can be decreased in response to chronic infection with HIV-1, varicella zoster, and pseudorabies. Decreases in GFAP expression have been reported in Down's syndrome, schizophrenia, bipolar disorder and depression.

The generally high abundance of GFAP in the CNS has led to a great interest in GFAP as a blood biomarker of acute injury to the brain and spinal cord in different types of disease mechanisms, such as traumatic brain injury and cerebrovascular disease. Elevated blood levels of GFAP are also found in neuroinflammatory diseases, such as multiple sclerosis and neuromyelitis optica, a disease targeting astrocytes. In a study of 22 child patients undergoing extracorporeal membrane oxygenation (ECMO), children with abnormally high levels of GFAP were 13 times more likely to die and 11 times more likely to suffer brain injury than children with normal GFAP levels.

Interactions
Glial fibrillary acidic protein has been shown to interact with MEN1 and PSEN1.

Isoforms
Although GFAP alpha is the only isoform which is able to assemble homomerically, GFAP has 8 different isoforms which label distinct subpopulations of astrocytes in the human and rodent brain. These isoforms include GFAP kappa, GFAP +1 and the currently best researched GFAP delta. GFAP delta appears to be linked with neural stem cells (NSCs) and may be involved in migration. GFAP+1 is an antibody which labels two isoforms. Although GFAP+1 positive astrocytes are supposedly not reactive astrocytes, they have a wide variety of morphologies including processes of up to 0.95mm (seen in the human brain). The expression of GFAP+1 positive astrocytes is linked with old age and the onset of AD pathology.

title: Glial fibrillary acidic protein


text:
Neurofilament

Neurofilaments (NF) are classed as type IV intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring 10 nm in diameter and many micrometers in length. Together with microtubules (~25 nm) and microfilaments (7 nm), they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into six types based on their gene organization and protein structure. Types I and II are the keratins which are expressed in epithelia. Type III contains the proteins vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP). Type IV consists of the neurofilament proteins NF-L, NF-M, NF-H and α-internexin. Type V consists of the nuclear lamins, and type VI consists of the protein nestin. The type IV intermediate filament genes all share two unique introns not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive type IV gene.

Any proteinaceous filament that extends in the cytoplasm of a nerve cell is also termed a neurofibril. This name is used in the neurofibrillary tangles of some neurodegenerative diseases.

Neurofilament proteins
The protein composition of neurofilaments varies widely across different animal phyla. Most is known about mammalian neurofilaments. Historically, mammalian neurofilaments were originally thought to be composed of just three proteins called neurofilament protein NF-L (low molecular weight; NF-L), NF-M (medium molecular weight; NF-M) and NF-H (high molecular weight; NF-H). These proteins were discovered from studies of axonal transport and are often referred to as the "neurofilament triplet". However, it is now clear that neurofilaments also contain the protein α-internexin and that neurofilaments in the peripheral nervous system can also contain the protein peripherin. (this is different from peripherin 2 that is expressed in the retina). Thus mammalian neurofilaments are heteropolymers of up to five different proteins: NF-L, NF-M, NF-H, α-internexin and peripherin. The five neurofilament proteins can co-assemble in different combinations in different nerve cell types and at different stages of development. The precise composition of neurofilaments in any given nerve cell depends on the relative expression levels of the neurofilament proteins in the cell at that time. For example, NF-H expression is low in developing neurons and increases postnatally in neurons with myelinated axons. In the adult nervous system neurofilaments in small unmyelinated axons contain more peripherin and less NF-H whereas neurofilaments in large myelinated axons contain more NF-H and less peripherin. The type III intermediate filament subunit, vimentin, is expressed in developing neurons and a few very unusual neurons in the adult in association with type IV proteins, such as the horizontal neurons of the retina. The triplet proteins are named based upon their relative size (low, medium, high). The apparent molecular mass of each protein determined by SDS-PAGE is greater than the mass predicted from the amino sequence. This is due to the anomalous electrophoretic migration of these proteins and is particularly extreme for neurofilament proteins NF-M and NF-H due to their high content of charged amino acids and extensive phosphorylation. All three neurofilament triplet proteins contain long stretches of polypeptide sequence rich in glutamic acid and lysine residues, and NF-M and especially NF-H also contain multiple tandemly repeated serine phosphorylation sites. These sites almost all contain the peptide lysine-serine-proline (KSP), and phosphorylation is normally found on axonal and not dendritic neurofilaments. Human NF-M has 13 of these KSP sites, while human NF-H is expressed from two alleles one of which produces 44 and the other 45 KSP repeats.

Neurofilament assembly and structure

Like other intermediate filament proteins, the neurofilament proteins all share a common central alpha helical region, known as the rod domain because of its rod-like tertiary structure, flanked by amino terminal and carboxy terminal domains that are largely unstructured. The rod domains of two neurofilament proteins dimerize to form an alpha-helical coiled coil. Two dimers associate in a staggered antiparallel manner to form a tetramer. This tetramer is believed to be the basic subunit (i.e. building block) of the neurofilament. Tetramer subunits associate side-to-side to form unit-length filaments, which then anneal end-to-end to form the mature neurofilament polymer, but the precise organization of these subunits within the polymer is not known, largely because of the heterogeneous protein composition and the inability to crystallize neurofilaments or neurofilament proteins. Structural models generally assume eight tetramers (32 neurofilament polypeptides) in a filament cross-section, but measurements of linear mass density suggest that this can vary.

The amino terminal domains of the neurofilament proteins contain numerous phosphorylation sites and appear to be important for subunit interactions during filament assembly. The carboxy terminal domains appear to be intrinsically disordered domains that lack alpha helix or beta sheet. The different sizes of the neurofilament proteins are largely due to differences in the length of the carboxy terminal domains. These domains are rich in acidic and basic amino acid residues. The carboxy terminal domains of NF-M and NF-H are the longest and are modified extensively by post-translational modifications such as phosphorylation and glycosylation in vivo. They project radially from the filament backbone to form a dense brush border of highly charged and unstructured domains analogous to the bristles on a bottle brush. These entropically flailing domains have been proposed to define a zone of exclusion around each filament, effectively spacing the filaments apart from their neighbors. In this way, the carboxy terminal projections maximize the space-filling properties of the neurofilament polymers. By electron microscopy, these domains appear as projections called sidearms that appear to contact neighboring filaments.

Neurofilament function
Neurofilaments are found in vertebrate neurons in especially high concentrations in axons, where they are all aligned in parallel along the long axis of the axon forming a continuously overlapping array. They have been proposed to function as space-filling structures that increase axonal diameter. Their contribution to axon diameter is determined by the number of neurofilaments in the axon and their packing density. The number of neurofilaments in the axon is thought to be determined by neurofilament gene expression and axonal transport. The packing density of the filaments is determined by their side-arms which define the spacing between neighboring filaments. Phosphorylation of the sidearms is thought to increase their extensibility, increasing the spacing between neighboring filaments by the binding of divalent cations between the sidearms of adjacent filaments

Early in development, axons are narrow processes that contain relatively few neurofilaments. Those axons that become myelinated accumulate more neurofilaments, which drives the expansion of their caliber. After an axon has grown and connected with its target cell, the diameter of the axon may increase as much as fivefold. This is caused by an increase in the number of neurofilaments exported from the nerve cell body as well as a slowing of their rate of transport. In mature myelinated axons, neurofilaments can be the single most abundant cytoplasmic structure and can occupy most of the axonal cross-sectional area. For example, a large myelinated axon may contain thousands of neurofilaments in one cross-section

Neurofilament transport
In addition to their structural role in axons, neurofilaments are also cargoes of axonal transport. Most of the neurofilament proteins in axons are synthesized in the nerve cell body, where they rapidly assemble into neurofilament polymers within about 30 minutes. These assembled neurofilament polymers are transported along the axon on microtubule tracks powered by microtubule motor proteins. The filaments move bidirectionally, i.e. both towards the axon tip (anterograde) and towards the cell body (retrograde), but the net direction is anterograde. The filaments move at velocities of up to 8 μm/s on short time scales (seconds or minutes), with average velocities of approximately 1 μm/s. However, the average velocity on longer time scales (hours or days) is slow because the movements are very infrequent, consisting of brief sprints interrupted by long pauses. Thus on long time scales neurofilaments move in the slow component of axonal transport.

Clinical and research applications
Numerous specific antibodies to neurofilament proteins have been developed and are commercially available. These antibodies can be used to detect neurofilament proteins in cells and tissues using immunofluorescence microscopy or immunohistochemistry. Such antibodies are widely used to identify neurons and their processes in histological sections and in tissue culture. The type VI intermediate filament protein Nestin is expressed in developing neurons and glia. Nestin is considered a marker of neuronal stem cells, and the presence of this protein is widely used to define neurogenesis. This protein is lost as development proceeds.

Neurofilament antibodies are also commonly used in diagnostic neuropathology. Staining with these antibodies can distinguish neurons (positive for neurofilament proteins) from glia (negative for neurofilament proteins).

There is also considerable clinical interest in the use of neurofilament proteins as biomarkers of axonal damage in diseases affecting the central nervous system. When neurons or axons degenerate, neurofilament proteins are released into the blood or cerebrospinal fluid. Immunoassays of neurofilament proteins in cerebrospinal fluid and plasma can thus serve as indicators of axonal damage in neurological disorders. NF-L levels in blood and CSF are therefore useful markers for disease monitoring in amyotrophic lateral sclerosis, multiple sclerosis, and more recently Huntington's disease. It has also been evaluated as a prognostic marker for functional outcome following acute ischemic stroke. Mutant mice with neurofilament abnormalities have phenotypes resembling amyotrophic lateral sclerosis. Recent work performed as a collaboration between EnCor Biotechnology Inc. and the University of Florida showed that the NF-L antibodies employed in the most widely used NF-L assays are specific for cleaved forms of NF-L generated by proteolysis induced by cell death. .

title: Neurofilament


text: User talk:68.74.179.46

title: User talk:68.74.179.46


text:
Nestin

Nestin may refer to:

 * Neštin, a village in Srem, Vojvodina, Serbia.
 * Nestin (protein), a type VI intermediate filament (IF) protein.
 * Neštin-class river minesweeper, a class of minesweeper built in service with Serbia and Hungary.

title: Nestin


text: User talk:68.62.166.206

title: User talk:68.62.166.206


text:
Livonian War

The Livonian War (1558–1583) was fought for control of Old Livonia (in the territory of present-day Estonia and Latvia). The Tsardom of Russia faced a varying coalition of the Dano-Norwegian Realm, the Kingdom of Sweden, and the Union (later Commonwealth) of the Grand Duchy of Lithuania and the Kingdom of Poland.

From 1558 to 1578, Russia dominated the region with early military successes at Dorpat (Tartu) and Narva. The Russian dissolution of the Livonian Confederation brought Poland–Lithuania into the conflict, and Sweden and Denmark intervened between 1559 and 1561. Swedish Estonia was established despite constant invasion from Russia, and Frederick II of Denmark bought the old Bishopric of Ösel–Wiek, which he placed under the control of his brother Magnus of Holstein. Magnus attempted to expand his Livonian holdings to establish the Russian vassal state, the Kingdom of Livonia, which nominally existed until his defection in 1576.

In 1576, Stephen Báthory became King of Poland as well as Grand Duke of Lithuania and turned the tide of the war with his successes between 1578 and 1581, including the joint Swedish–Polish–Lithuanian offensive at the Battle of Wenden. That was followed by an extended campaign through Russia, culminating in the long and difficult Siege of Pskov. Under the 1582 Truce of Jam Zapolski, which ended the war between Russia and Poland–Lithuania, Russia lost all of its former holdings in Livonia and Polotsk to Poland–Lithuania. The following year, Sweden and Russia signed the Truce of Plussa, with Sweden gaining most of Ingria and northern Livonia while retaining the Duchy of Estonia.

Pre-war Livonia

By the mid-16th century, economically prosperous Old Livonia had become a region organised into the decentralised and religiously divided Livonian Confederation. Its territories consisted of the Livonian branch of the Teutonic Order, the prince-bishoprics of Dorpat (Tartu), Ösel–Wiek, as well as Courland, the Archbishopric of Riga and the city of Riga. Together with Riga, the cities of Dorpat (Tartu) and Reval (Tallinn), along with the knightly estates, enjoyed privileges enabling them to act almost independently. The only common institutions of the Livonian estates were the regularly held common assemblies known as Landtags. As well as a divided political administration, there were also persistent rivalries between the Archbishop of Riga and the Landmeister of the Order for hegemony. A schism had existed within the Order since the Reformation had spread to Livonia in the 1520s, although the transformation of the country into a Lutheran region was a gradual process, resisted by part of the Order that to a varying degree remained sympathetic to Roman Catholicism. As war approached, Livonia had a weak administration subject to internal rivalries, lacked any powerful defences or outside support, and was surrounded by monarchies pursuing expansionist policies. Robert I. Frost notes of the volatile region: "Racked with internal bickering and threatened by the political machinations of its neighbours, Livonia was in no state to resist an attack."

The Order's Landmeister and the Gebietigers, as well as the owners of Livonian estates, were all lesser nobles who guarded their privileges and influence by preventing the creation of a higher, more powerful noble class. Only the archbishopric of Riga successfully overcame resistance of the lesser nobles. Wilhelm von Brandenburg was appointed as Archbishop of Riga and Christoph von Mecklenburg as his Coadjutor, with the help of his brother Albert (Albrecht) of Brandenburg–Ansbach, the former Prussian Hochmeister who had secularised the southern Teutonic Order state and in 1525 established himself as duke in Prussia. Wilhelm and Christoph were to pursue Albert's interests in Livonia, among which was the establishment of a hereditary Livonian duchy styled after the Prussian model. At the same time the Order agitated for its re-establishment ("Rekuperation") in Prussia, opposed secularization, and creation of a hereditary duchy.

Aspirations of Livonia's neighbours
By the time the Livonian War broke out, the Hanseatic League had already lost its monopoly on the profitable and prosperous Baltic Sea trade. While still involved and with increasing sales, it now shared the market with European mercenary fleets, most notably from the Dutch Seventeen Provinces and France. The Hanseatic vessels were no match for contemporary warships, and since the league was unable to maintain a large navy because of a declining share of trade, its Livonian members Riga, Reval (Tallinn), and trading partner Narva were left without suitable protection. The Danish navy, the most powerful in the Baltic Sea, controlled the entrance to the Baltic Sea, collected requisite tolls, and held the strategically important Baltic Sea islands of Bornholm and Gotland.

A long bar of Danish territories in the south and lack of sufficient year-round ice-free ports severely limited Sweden's access to Baltic trade. Nevertheless, the country prospered due to exports of timber, iron, and most notably copper, coupled with the advantages of a growing navy and proximity to the Livonian ports across the narrow Gulf of Finland. Before the Livonian War, Sweden had sought expansion into Livonia, but the intervention of the Russian tsar temporarily stalled these efforts through the Russo-Swedish War of 1554–1557, which culminated in the 1557 Treaty of Novgorod.

Through its absorption of the principalities of Novgorod (1478) and Pskov (1510), the Tsardom of Russia had become Livonia's eastern neighbour and grown stronger after annexing the khanates of Kazan (1552) and Astrakhan (1556). The conflict between Russia and the Western powers was exacerbated by Russia's isolation from sea trade. The new Ivangorod port – built in 1550 during the reign of Tsar Ivan IV on the eastern shore of the Narva River – was considered unsatisfactory on account of its shallow waters. Thereafter the tsar demanded that the Livonian Confederation pay about 6,000 marks to keep the Bishopric of Dorpat, based on the claim that every adult male had paid Pskov one mark when it had been an independent state. The Livonians eventually promised to pay this sum to Ivan by 1557, but were sent from Moscow when they failed to do so, ending negotiations. Ivan continued to point out that the existence of the Order required passive Russian support, and was quick to threaten use of military force if necessary. He aimed to establish a corridor between the Baltic and the new territories on the Caspian Sea, because if Russia were to engage in open conflict with major western powers, it would need imports of more sophisticated weaponry.

The Polish King and Lithuanian Grand Duke Sigismund II Augustus was wary of Russian expansionist aspirations. Expansion of Russia into Livonia would have meant not only a stronger political rival but also loss of lucrative trade routes. Therefore, Sigismund supported his cousin Wilhelm von Brandenburg, archbishop of Riga, in his conflicts with Wilhelm von Fürstenberg, the Livonian Order's landmeister. Sigismund hoped that Livonia, just like the Duchy of Prussia under Duke Albert, would become a vassal state of Poland–Lithuania. With weak support in Livonia, von Brandenburg had to largely rely on external allies. Among his few Livonian supporters was landmarschall Jasper von Munster, with whom he planned an April 1556 attack on his opponents that would involve military aid from both Sigismund and Albert. However, Sigismund hesitated over participation in the action, fearing that it would leave the Kiev Voivodeship exposed to a pending Russian attack. When von Fürstenberg learned of the plan, he led a force into the archbishopric of Riga and in June 1556 captured the main strongholds of Kokenhusen and Ronneburg. Jasper von Munster fled to Lithuania, but von Brandenburg and Christoph von Mecklenburg were captured and detained at Adsel and Treiden. This resulted in a diplomatic mission to petition for their release being dispatched by the Pomeranian dukes, the Danish King, Emperor Ferdinand I, and the estates of the Holy Roman Empire. A cross-party meeting in Lübeck to resolve the conflict was scheduled for 1 April 1557, but was cancelled due to quarrels between Sigismund and the Danish envoys. Sigismund used the killing of his envoy Lancki by the landmeister's son as an excuse to invade the southern portion of Livonia with an army of around 80,000. He forced the competing parties in Livonia to reconcile at his camp in Pozvol in September 1557. There they signed the Treaty of Pozvol, which created a mutual defensive and offensive alliance, with its primary target Russia, and provoked the Livonian War.

Russian invasion of Livonia

Ivan IV regarded the Livonian Confederation's approach to the Polish–Lithuanian union for protection under the Treaty of Pozvol as casus belli. In 1554 Livonia and Russia had signed a fifteen-year truce in which Livonia agreed not to enter into an alliance with Poland–Lithuania. On 22 January 1558, Ivan reacted with the invasion of Livonia. The Russians were seen by local peasants as liberators from the German control of Livonia. Many Livonian fortresses surrendered without resistance while Russian troops took Dorpat (Tartu) in May, Narva in July and laid siege to Reval (Tallinn). Reinforced by 1,200 Landsknechts, 100 gunners, and ammunition from Germany, Livonian forces successfully retook Wesenberg (Rakvere) along with a number of other fortresses. Although the Germans raided Russian territory, Dorpat (Tartu), Narva, and many lesser fortresses remained in Russian hands. The initial Russian advance was led by the Khan of Qasim Shahghali, with two other Tatar princes at the head of a force that included Russian boyars, Tatar, and Pomestnoe cavalry, as well as Cossacks, who at that time were mostly armed foot soldiers. Ivan gained further ground in campaigns during the years 1559 and 1560. In January 1559, Russian forces again invaded Livonia. A six-month truce covering May to November was signed between Russia and Livonia while Russia fought in the Russo-Crimean Wars.

Prompted by the Russian invasion, Livonia first unsuccessfully sought help from Emperor Ferdinand I, then turned to Poland–Lithuania. Landmeister von Fürstenburg fled to Poland–Lithuania to be replaced by Gotthard Kettler. In June 1559, the estates of Livonia came under Polish–Lithuanian protection through the first Treaty of Vilnius. The Polish sejm refused to agree to the treaty, believing it to be a matter affecting only the Grand Duchy of Lithuania. In January 1560, Sigismund sent ambassador Martin Volodkov to the court of Ivan in Moscow in an attempt to stop the Russian cavalry rampaging through rural Livonia.

Russian successes followed similar patterns featuring a multitude of small campaigns, with sieges where musketmen played a key role in destroying wooden defences with effective artillery support. The Tsar's forces took important fortresses like Fellin (Viljandi), yet lacked the means to gain the major cities of Riga, Reval (Tallinn), or Pernau (Pärnu). The Livonian knights suffered a disastrous defeat by the Russians at the Battle of Ērģeme in August 1560. Some historians believe the Russian nobility were split over the timing of the invasion of Livonia.

Eric XIV, the new King of Sweden, turned down Kettler's requests for assistance, along with a similar request from Poland. Kettler turned to Sigismund for help. The weakened Livonian Order was dissolved by the second Treaty of Vilnius in 1561. Its lands were secularised as the Duchy of Livonia and Duchy of Courland and Semigallia and assigned to the Grand Duchy of Lithuania. Kettler became the first Duke of Courland, in doing so converting to Lutheranism. Included in the treaty was the Privilegium Sigismundi Augusti by which Sigismund guaranteed the Livonian estates privileges including religious freedom with respect to the Augsburg Confession, the Indygenat, and continuation of the traditional German administration. The terms regarding religious freedom forbade any regulation of the Protestant order by religious or secular authorities.

Some members of the Lithuanian nobility opposed the growing Polish–Lithuanian union and offered the Lithuanian crown to Ivan IV. The Tsar publicly advertised this option, either because he took the offer seriously, or because he needed time to strengthen his Livonian troops. Throughout 1561, a Russo-Lithuanian truce (with a scheduled expiration date of 1562) was respected by both sides.

Danish and Swedish interventions
In return for a loan and a guarantee of Danish protection, Bishop Johann von Münchhausen signed a treaty on 26 September 1559 giving Frederick II of Denmark-Norway the right to nominate the bishop of Ösel–Wiek, an act which amounted to the sale of these territories for 30,000 thalers. Frederick II nominated his brother, Duke Magnus of Holstein as bishop, who then took possession in April 1560. Lest Danish efforts create more insecurity for Sweden, Denmark-Norway made another attempt to mediate a peace in the region. Magnus at once pursued his own interests, purchasing the Bishopric of Courland without Frederick's consent and trying to expand into Harrien–Wierland (Harju and Virumaa). This brought him into direct conflict with Eric.

In 1561, Swedish forces arrived and the noble corporations of Harrien–Wierland and Jerwen (Järva) yielded to Sweden to form the Duchy of Estonia. Reval (Tallinn), similarly, accepted Swedish rule. Denmark dominated the Baltic, and Sweden wished to challenge this by gaining territory on the Eastern side of the Baltic. Doing so would help Sweden control the West's trade with Russia. This helped to precipitate the Northern Seven Years' War since in 1561, Frederick II had already protested against Swedish presence in Reval (Tallinn), claiming historical rights relating to Danish Estonia. When Eric XIV's forces seized Pernau (Pärnu) in June 1562, his diplomats tried to arrange Swedish protection for Riga, which brought him into conflict with Sigismund.

Sigismund maintained close relations with Eric XIV's brother, John, Duke of Finland (later John III), and in October 1562 John married Sigismund's sister, Catherine, thereby preventing her marrying Ivan IV. While Eric XIV had approved the marriage, he was upset when John lent Sigismund 120,000 dalers and received seven Livonian castles as security. This incident led to John's capture and imprisonment in August 1563 on Eric XIV's behalf, whereupon Sigismund allied with Denmark and Lübeck against Eric XIV in October the same year.

1562–1570
The intervention of Denmark-Norway, Sweden, and Poland-Lithuania into Livonia began a period of struggle for control of the Baltic, known contemporaneously as the dominium maris baltici. While the initial war years were characterised by intensive fighting, a period of low-intensity warfare began in 1562 and lasted until 1570 when fighting once more intensified. Denmark, Sweden, and to some extent Poland–Lithuania were occupied with the Nordic Seven Years' War (1563–1570) taking place in the Western Baltic, but Livonia remained strategically important. In 1562, Denmark and Russia concluded the Treaty of Mozhaysk, respecting each other's claims in Livonia and maintaining amicable relations. In 1564, Sweden and Russia concluded a seven-years truce. Both Ivan IV and Eric XIV showed signs of mental disorder, with Ivan IV turning against part of the Tsardom's nobility and people with the oprichina that began in 1565, leaving Russia in a state of political chaos and civil war.

Russian war with Lithuania

When the Russo-Lithuanian truce expired in 1562, Ivan IV rejected Sigismund's offer of an extension. The Tsar had used the period of the truce to build up his forces in Livonia, and he invaded Lithuania. His army raided Vitebsk and, after a series of border clashes, took Polotsk in 1563. Lithuanian victories came at the Battle of Ula in 1564 and at Czasniki (Chashniki) in 1567, a period of intermittent conflict between the two sides. Ivan continued to gain ground among the towns and villages of central Livonia but was held at the coast by Lithuania. The defeats of Ula and Czasniki, along with the defection of Andrey Kurbsky, led Ivan IV to move his capital to the Alexandrov Kremlin while the perceived opposition against him was repressed by his oprichniki.

A "grand" party of diplomats left Lithuania for Moscow in May 1566. Lithuania was prepared to split Livonia with Russia, with a view to a joint offensive to drive Sweden from the area. However, this was seen as a sign of weakness by Russian diplomats, who instead suggested that Russia take the whole of Livonia, including Riga, through the ceding of Courland in southern Livonia and Polotsk on the Lithuanian–Russian border. The transfer of Riga, and the surrounding entrance to the River Dvina, troubled the Lithuanians, since much of their trade depended on safe passage through it and they had already built fortifications to protect it. Ivan expanded his demands in July, calling for Ösel in addition to Dorpat (Tartu) and Narva. No agreement was forthcoming and a ten-day break was taken in negotiations, during which time various Russian meetings were held (including the zemsky sobor, the Assembly of the Land) to discuss the issues at stake. Within the Assembly, the church's representative stressed the need to "keep" Riga (though it had not yet been conquered), while the Boyars were less keen on an overall peace with Lithuania, noting the danger posed by a joint Polish-Lithuanian state. Talks were then halted and hostilities resumed upon the return of the ambassadors to Lithuania.

In 1569, the Treaty of Lublin unified Poland and Lithuania into the Polish–Lithuanian Commonwealth. The Duchy of Livonia, tied to Lithuania in real union since the Union of Grodno in 1566, came under Polish–Lithuanian joint sovereignty. In June 1570 a three-year truce was signed with Russia. Sigismund II, the Commonwealth's first King, died in 1572 leaving the Polish throne with no clear successor for the first time since 1382 and thus began the first free election in Polish history. Some Lithuanian nobles, in an effort to retain Lithuanian autonomy, proposed a Russian candidate. Ivan, however, demanded the return of Kiev, an Orthodox coronation, and a hereditary monarchy in parallel to Russia's, with his son, Feodor, as King. The electorate rejected these demands and instead chose Henry of Valois (Henryk Walezy), brother of King Charles IX of France.

Russian war with Sweden
In 1564, Sweden and Russia agreed the Treaty of Dorpat, whereby Russia recognised Sweden's right to Reval (Tallinn) and other castles, and Sweden accepted Russia's patrimony over the rest of Livonia. A seven-year truce was signed between Russia and Sweden in 1565. Eric XIV of Sweden was overthrown in 1568 after he killed several nobles in the Sture Murders (Sturemorden) of 1567, and was replaced by his half-brother John III. Both Russia and Sweden had other problems and were keen to avoid an expensive escalation of the war in Livonia. Ivan IV had requested the delivery of John's wife, the Polish-Lithuanian princess Catherine Jagellonica, to Russia, since he had competed with John to marry into the Lithuanian-Polish royal family. In July 1569 John sent a party to Russia, led by Paul Juusten, Bishop of Åbo, which arrived in Novgorod in September, following the arrival in Moscow of the ambassadors sent to Sweden in 1567 by Ivan to retrieve Catherine. Ivan refused to meet with the party himself, forcing them to negotiate instead with the Governor of Novgorod. The Tsar requested that Swedish envoys should greet the governor as 'the brother of their king', but Juusten refused to do so. The Governor then ordered an attack on the Swedish party, that their clothes and money be taken, and that they be deprived of food and drink and be paraded naked through the streets.

Although the Swedes were also to be moved to Moscow, this occurred at the same time Ivan and his oprichniki were on their way to launch an assault on Novgorod in northern Russia. In an act of vengeance against the perceived treason of the local Orthodox church in Novgorod, Ivan's forces launched an attack on the city, where 2,000−15,000 people were killed.

On his return to Moscow in May 1570, Ivan refused to meet the Swedish party, and with the signing of a three-year truce in June 1570 with the Commonwealth he no longer feared war with Poland–Lithuania. Russia considered the delivery of Catherine to be a precondition of any deal, and the Swedes agreed to meet in Novgorod to discuss the matter. According to Juusten, at the meeting the Russians demanded the Swedes to abandon their claim to Reval (Tallinn), provide two or three hundred cavalry when required, pay 10,000 thaler in direct compensation, surrender Finnish silver mines near the border with Russia, and allow the Tsar to style himself "Lord of Sweden". The Swedish party left following an ultimatum from Ivan that Sweden should cede its territory in Livonia or there would be war. Juusten was left behind while John rejected Ivan's demands, and war broke out anew.

Impact of the Northern Seven Years' War
Quarrels between Denmark-Norway and Sweden led to the Northern Seven Years' War in 1563, which ended in 1570 with the Treaty of Stettin. Primarily fought in western and southern Scandinavia, the war involved important naval battles fought in the Baltic. When Danish-held Varberg surrendered to Swedish forces in 1565, 150 Danish mercenaries escaped the subsequent massacre of the garrison by defecting to Sweden. Among them was Pontus de la Gardie, who thereafter became an important Swedish commander in the Livonian War. Livonia was also affected by the naval campaign of Danish admiral Peder Munk, who bombarded Swedish Reval (Tallinn) from sea in July 1569.

The Treaty of Stettin made Denmark the supreme and dominating power in Northern Europe, yet failed to restore the Kalmar Union. Unfavourable conditions for Sweden led to a series of conflicts that only ended with the Great Northern War in 1720. Sweden agreed to turn over her possessions in Livonia in return for a payment by Holy Roman Emperor Maximilian II. Maximilian failed to pay the promised compensation, however, and thereby lost his influence on Baltic affairs. The terms of the treaty regarding Livonia were ignored, and thus the Livonian War continued. From Ivan's point of view, the treaty enabled the powers involved to form an alliance against him, now that they were no longer fighting each other.

1570–1577: Russian dominance and the Kingdom of Livonia
During the early 1570s, King John III of Sweden faced a Russian offensive on his positions in Estonia. Reval (Tallinn) withstood a Russian siege in 1570 and 1571, but several smaller towns were taken by Russian forces. On 23 January a Swedish army of 700 infantry and 600 cavalry under command of Clas Åkesson Tott (the Elder) clashed with a Russian and Tartar army of 16,000 men under the command of Khan Sain-Bulat at the Battle of Lode by the village of Koluvere. The Russian advance concluded with the sacking of Weissenstein (Paide) in 1573, where, after its capture, the occupying forces roasted some of the leaders of the Swedish garrison alive, including the commander. This triggered a retaliatory campaign by John centred on Wesenberg, to which the army departed in November 1573 with Klas Åkesson Tott in overall command and Pontus de la Gardie as field commander. There were also Russian raids into Finland, including one as far as Helsingfors (Helsinki) in 1572. A two-year truce on this front was signed in 1575.

John's counter-offensive stalled at the siege of Wesenberg in 1574, when German and Scottish units of the Swedish army turned against each other. This failure has also been blamed on the difficulties of fighting in the bitter winter conditions, particularly for the infantry. The war in Livonia was a great financial burden for Sweden, and by the end of 1573, Sweden's German mercenaries were owed 200,000 daler. John gave them the castles of Hapsal, Leal, and Lode as security, but when he failed to pay they were sold to Denmark.

Meanwhile, efforts by Magnus to besiege Swedish-controlled Reval (Tallinn) were faltering, with support from neither Ivan nor Magnus' brother, Frederick II of Denmark forthcoming. Ivan's attention was focused elsewhere, while Frederick's reluctance perhaps stemmed from a new spirit of Swedish–Danish unity that made him unwilling to invade Livonia on behalf of Magnus, whose state was a vassal of Russia. The siege was abandoned in March 1571, whereupon Swedish action in the Baltic escalated, with the passive backing of Sigismund, John's brother-in-law.

At the same time Crimean Tatars devastated Russian territories and burned and looted Moscow during the Russo-Crimean Wars. Drought and epidemics had fatally affected the Russian economy while oprichnina had thoroughly disrupted the government. Following the defeat of Crimean and Nogai forces in 1572, oprichnina was wound down and with it the way Russian armies were formed also changed. Ivan IV had introduced a new strategy whereby he relied on tens of thousands of native troops, Cossacks and Tatars instead of a few thousand skilled troops and mercenaries, as was the practice of his adversaries.

Ivan's campaign reached its height in 1576 when another 30,000 Russian soldiers crossed into Livonia in 1577 and devastated Danish areas in retaliation for the Danish acquisition of Hapsal, Leal, and Lode. Danish influence in Livonia ceased, as Frederick accepted deals with Sweden and Poland to end nominal Danish involvement. Swedish forces were besieged in Reval (Tallinn) and central Livonia raided as far as Dünaburg (Daugavpils), formally under Polish–Lithuanian control since the 1561 Treaty of Vilnius. The conquered territories submitted to Ivan or his vassal, Magnus, declared monarch of the Kingdom of Livonia in 1570. Magnus defected from Ivan IV during the same year, having started to appropriate castles without consulting the Tsar. When Kokenhusen (Koknese) submitted to Magnus to avoid fighting Ivan IV's army, the Tsar sacked the town and executed its German commanders. The campaign then focussed on Wenden (Cēsis, Võnnu), "the heart of Livonia", which as the former capital of the Livonian Order was not only of strategic importance, but also symbolic of Livonia itself.

Swedish and Polish–Lithuanian alliance and counter-offensives
In 1576, the Transylvanian prince Stephen Báthory became King of Poland and Grand Duke of Lithuania after a contested election to the joint Polish–Lithuanian throne with the Habsburg Emperor Maximilian II. Both Báthory's fiancée Anna Jagiellon and Maximilian II had been proclaimed elected to the same throne in December 1575, three days apart; Maximilan's death in October 1576 prevented the conflict from escalating. Báthory, ambitious to expel Ivan IV from Livonia, was constrained by the opposition of Danzig (Gdansk), which resisted Báthory's accession with Danish support. The ensuing Danzig War of 1577 ended when Báthory conceded further autonomous rights to the city in return for a payment of 200,000 zlotys. For a further 200,000 zloty payment, he appointed Hohenzollern George Frederick as administrator of Prussia and secured the latter's military support in the planned campaign against Russia.

Báthory received only few soldiers from his Polish vassals and was forced to recruit mercenaries, primarily Poles, Hungarians, Bohemians, Germans, and Wallachians. A separate Szekler brigade fought in Livonia.

Swedish King John III and Stephen Báthory allied against Ivan IV in December 1577, despite problems caused by the death of Sigismund which meant that the issue of the substantial inheritance due to John's wife, Catherine, had not been resolved. Poland also claimed the whole of Livonia, without accepting Swedish rule of any part of it. The 120,000 daler lent in 1562 had still not been repaid, despite Sigismund's best intentions to settle it.

By November, Lithuanian forces moving northward had captured Dünaburg while a Polish–Swedish force took the town and castle of Wenden in early 1578. Russian forces failed to retake the town in February, an attack followed by a Swedish offensive, targeting Pernau (Pärnu), Dorpat, and Novgorod among others. In September, Ivan responded by sending in an army of 18,000 men, who recaptured Oberpahlen (Põltsamaa) from Sweden and then marched on Wenden. Upon their arrival at Wenden, the Russian army laid siege to the town, but was met by a relief force of around 6,000 German, Polish, and Swedish soldiers. In the ensuing Battle of Wenden, Russian casualties were severe with armaments and horses captured, leaving Ivan IV with his first serious defeat in Livonia.

Báthory accelerated the formation of the hussars, a new well-organised cavalry troop that replaced the feudal levy. Similarly, he improved an already effective artillery system and recruited cossacks. Báthory gathered 56,000 troops, 30,000 of them from Lithuania, for his first assault on Russia at Polotsk, as part of a wider campaign. With Ivan's reserves in Pskov and Novgorod to guard against a possible Swedish invasion, the city fell on 30 August 1579. Báthory then appointed a close ally and powerful member of his court, Jan Zamoyski, to lead a force of 48,000, including 25,000 men from Lithuania, against the fortress of Velikie Luki which he went on to capture on 5 September 1580. Without further significant resistance, garrisons such as Sokol, Velizh, and Usvzat fell quickly. In 1581, the force besieged Pskov, a well-fortified and heavily defended fortress. However, financial support from the Polish parliament was dropping, and Báthory failed to lure Russian forces in Livonia out into open field before the onset of winter. Not realising that the Polish–Lithuanian advance was on the wane, Ivan signed the Truce of Jam Zapolski.

The failure of the Swedish siege of Narva in 1579 led to Pontus de la Gardie's appointment as commander-in-chief. The towns of Kexholm and Padise were taken by Swedish forces in 1580, then in 1581, concurrent with the fall of Wesenberg, a mercenary army hired by Sweden recaptured the strategic city of Narva. A target of John III's campaigns, since it could be attacked by both land and sea, the campaign made use of Sweden's considerable fleet but later arguments over formal control in the long term hampered any alliance with Poland. Following la Gardie's taking of the city, and in retaliation for previous Russian massacres, 7,000 Russians were killed according to Russow's contemporary chronicle. The fall of Narva was followed by those of Ivangorod, Jama, and Koporye, leaving Sweden content with its gains in Livonia.

Truces of Jam Zapolski and Plussa
Subsequent negotiations led by Jesuit papal legate Antonio Possevino resulted in the 1582 Truce of Jam Zapolski between Russia and the Polish–Lithuanian Commonwealth. This was a humiliation for the Tsar, in part because he requested the truce. Under the agreement Russia would surrender all areas in Livonia it still held and the city of Dorpat (Tartu) to the Polish–Lithuanian Commonwealth, while Polotsk would remain under Commonwealth control. Any captured Swedish territory—specifically Narva—could be retained by the Russians and Velike Luki would be returned from Báthory's control to Russia. Possevino made a half-hearted attempt to get John III's wishes taken into consideration, but this was vetoed by the Tsar, probably in collusion with Báthory. The armistice, which fell short of a full peace arrangement, was to last ten years and was renewed twice, in 1591 and 1601. Báthory failed in his attempts to pressure Sweden into relinquishing its gains in Livonia, particularly Narva.

Following a decision by John, the war with Russia ended when the Tsar concluded the Truce of Plussa (Plyussa, Pljussa, Plusa) with Sweden on 10 August 1583. Russia relinquished most of Ingria, leaving Narva and Ivangorod as well under Swedish control. Originally scheduled to last three years, the Russo-Swedish truce was later extended until 1590. During the negotiations, Sweden made vast demands for Russian territory, including Novgorod. Whilst these conditions were probably only for the purposes of negotiation, they may have reflected Swedish aspirations of territory in the region.

Aftermath
The post-war Duchy of Courland and Semigallia south of the Düna (Daugava) river experienced a period of political stability based on the 1561 Treaty of Vilnius, later modified by the 1617 Formula regiminis and Statuta Curlandiæ, which granted indigenous nobles additional rights at the duke's expense. North of the Düna, Báthory reduced the privileges Sigismund had granted the Duchy of Livonia, regarding the regained territories as the spoils of war. Riga's privileges had already been reduced by the Treaty of Drohiczyn in 1581. Polish gradually replaced German as the administrative language and the establishment of voivodeships reduced the Baltic German administration. The local clergy and the Jesuits in Livonia embraced the counter-reformation in a process assisted by Báthory, who gave the Roman Catholic Church revenues and estates confiscated from Protestants as well as initiating a largely unsuccessful recruitment campaign for Catholic colonists. Despite these measures, the Livonian population did not convert en masse, while the Livonian estates in Poland–Lithuania were alienated.

In 1590, the Russo-Swedish truce of Plussa expired and fighting resumed while the ensuing Russo-Swedish War of 1590–5 ended with the Treaty of Teusina (Tyavzino, Tyavzin), under which Sweden had to cede Ingria and Kexholm to Russia. The Swedish–Polish alliance began to crumble when the Polish King and Grand Duke of Lithuania Sigismund III, who as son of John III of Sweden (died 1592) and Catherine Jagellonica, was the successor to the Swedish throne, met with resistance from a faction led by his uncle, Charles of Södermanland (later Charles IX), who claimed regency in Sweden for himself. Sweden descended into a civil war in 1597, followed by the 1598–1599 war against Sigismund, which ended with the deposition of Sigismund by the Swedish riksdag.

Local nobles turned to Charles for protection in 1600 when the conflict spread to Livonia, where Sigismund had tried to incorporate Swedish Estonia into the Duchy of Livonia. Charles then expelled the Polish forces from Estonia and invaded the Livonian duchy, starting a series of Polish–Swedish wars. At the same time, Russia was embroiled in civil war over the vacant Russian throne ("Time of Troubles") when none of the many claimants had prevailed. This conflict became intertwined with the Livonian campaigns when Swedish and Polish–Lithuanian forces intervened on opposite sides, the latter starting the Polish–Muscovite War. Charles IX's forces were expelled from Livonia after major setbacks at the battles of Kokenhausen(1601) and Kircholm (1605). During the later Ingrian War, Charles' successor Gustavus Adolphus retook Ingria and Kexholm which were formally ceded to Sweden under the 1617 Treaty of Stolbovo along with the bulk of the Duchy of Livonia. In 1617, when Sweden had recovered from the Kalmar War with Denmark, several Livonian towns were captured, but only Pernau (Pärnu) remained under Swedish control after a Polish–Lithuanian counter-offensive. A second campaign then started with the capture of Riga in 1621 and expelled Polish–Lithuanian forces from most of Livonia, where the dominion of Swedish Livonia was created. Swedish forces then advanced through Royal Prussia and Poland–Lithuania accepted Swedish gains in Livonia in the 1629 Treaty of Altmark.

The Danish province of Øsel was ceded to Sweden under the 1645 Treaty of Brömsebro, which ended the Torstenson War, one theatre of the Thirty Years' War. It was retained after the Peace of Oliva and the Treaty of Copenhagen, both in 1660. The situation remained unchanged until 1710 when Estonia and Livonia capitulated to Russia during the Great Northern War, an action formalised in the Treaty of Nystad (1721).

title: Livonian War


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GI cocktail

A gastrointestinal cocktail, (also known as a GI cocktail or gastric cocktail), is a mixture of medications used to treat symptoms of dyspepsia. The GI cocktail generally contains a mixture of viscous lidocaine, an antacid, and an anticholinergic. The GI cocktail is commonly prescribed in the hospital or emergency department, and has been used to help distinguish chest pain as either gastrointestinal or cardiac. While it has been widely used in the treatment of dyspepsia, studies have suggested that the GI cocktail is only as effective as antacids alone.

The "GI cocktail" does not refer to a specific product. Rather, it refers to a mixture of viscous lidocaine, an antacid, and an anticholinergic. Viscous lidocaine works as an anesthetic to numb pain in the throat, esophagus, and stomach. Antacids work to neutralize stomach acid. Anticholinergics work to ease symptoms that accompany dyspepsia including nausea, vomiting, and abdominal cramping.

Contents and dosing
The GI cocktail is a mixture of a viscous anesthetic, an antacid, and an anticholinergic. Common viscous anesthetics use are viscous lidocaine or xylocaine. Common antacids used are magnesium hydroxide, aluminum hydroxide, or simethicone (more commonly known as Mylanta or Maalox). Common anticholinergics used are hyoscyamine sulfate, atropine sulfat e, scopolamine hydrobromide, and phenobarbital (more commonly known as Donnatal). Typical dosing is 5ml of viscous anesthetic, 30ml of liquid antacid, and 10ml of anticholinergic.

Medical uses
The GI cocktail is commonly prescribed in the hospital or emergency department to treat symptoms of dyspepsia. These symptoms include: belching, heartburn, chest pain, abdominal discomfort, abdominal bloating, nausea, loss of appetite, and flatulence. Dyspepsia itself is not an illness, rather it is an indicator of chronic underlying gastrointestinal issues such as peptic ulcer disease, gastro-esophageal reflux disease, h.pylori gastritis, gastroparesis, or upper gastrointestinal cancers. Dyspepsia can additionally be contributed to medications such as potassium supplements, NSAIDs, digitalis, iron, glucocorticoids, and colchicine, as well as lifestyle factors such as diet, stress, and cigarette smoking.

Side effects
Some people experience side effects that are the result of the individual medications used to make the GI cocktail. They include:

Viscous lidocaine: Antacid: Anticholinergic:
 * Allergic reaction such as rash, itching, or hives. Swelling of the lips, tongue, mouth, face, and throat is possible in severe cases
 * Numbness/tingling
 * Visual changes
 * Nervousness
 * Confusion
 * Chest pain
 * Seizures
 * Difficulty breathing
 * Allergic reaction such as rash, itching, or hives. Swelling of the lips, tongue, mouth, face, and throat is possible in severe cases
 * Stomach cramps
 * Nausea
 * Constipation
 * Diarrhea
 * Headache
 * Dry mouth
 * Blurry vision
 * Dry eyes
 * Constipation
 * Urinary retention
 * Dizziness
 * Confusion
 * Heart arrhythmia

Efficacy
Prior studies regarding the GI cocktail for management of dyspepsia in the emergency department have varied in quality of methodology and have demonstrated mixed results. A 1990 single-blind study performed by Welling and Watson compared 30 mL of antacid with or without the addition of 15 mL of viscous lidocaine and concluded that the addition of viscous lidocaine provided a significantly greater degree of immediate pain relief than antacids alone in patients with dyspepsia. A 2004 single-blind study performed by Vike and Davis, compared treatment with antacids plus either viscous lidocaine or benzocaine solution and did not find a statistically significant difference between the two treatment arms – however the study lacked an antacid monotherapy arm. A robust double-blind clinical trial performed in 2003 by Berman et al. compared 30 mL of antacid monotherapy, antacid with the addition of 10 ml of an anticholinergic, and an antacid with anticholinergic with the addition of 10 mL of 2% viscous lidocaine. That study demonstrated no statistically significant difference in pain relief between treatment arms and concluded that all treatments were clinically effective. The ultimately recommended antacid monotherapy alone in the treatment of dyspepsia.

title: GI cocktail


text: User talk:24.194.165.82

title: User talk:24.194.165.82


text: User talk:68.12.112.248

title: User talk:68.12.112.248


text: User talk:68.162.212.156

title: User talk:68.162.212.156


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Middleport, Staffordshire

Middleport is a residential and industrial district in the city of Stoke-on-Trent, England. Middleport lies to the west of Burslem, between Burslem and the Newcastle-under-Lyme district of Porthill. To the north is Tunstall and to the south Cobridge and Etruria. Middleport conjoins Longport.

Middleport is primarily residential, with distinctive Victorian terraced houses. However, it also a working industrial district and contains several potteries: ranging from Middleport Pottery, owned by the Prince's Regeneration Trust and claimed to be the only working Victorian pottery remaining in the city, and Steelite, a large manufacturer of hotelware.

The Trent and Mersey Canal and a key path of the National Cycle Network run through Middleport. The line of the canal through the City of Stoke-on-Trent is a linear conservation area. Middleport contains one of the nation's richest stretches of canalside industrial heritage. Since 1990 the canal area has benefited from around £1m of Groundwork funding, and £4m of Townscape Heritage funding. Clarice Cliff's Newport Pottery, where she produced some of her most famous work, was adjacent to the canal and an artist-designed 12-foot steel markerpost identifies the location.

Middleport is an area that is strategic to the regeneration of the city, as it sits in the centre of a ring of imminent projects totalling around £250m: the Chatterley Valley scheme, the Etruria Valley scheme, the regeneration of Burslem town centre, and a proposed major "park and ride" interchange and business-park on the site of the old Shelton Bar steel rolling-mill.

Middleport piloted a community warden service in 2002 & 2003; as a result, crime dropped by 80 per cent. The service was subsequently extended across Stoke-on-Trent and adopted in other cities.

Middleport features in several of the novels of Arnold Bennett, and the film version of his The Card was filmed in Middleport with Alec Guinness.

Middleport Park Bowling Club has a national reputation and has won several national trophies.

Middleport Matters (founded 2015) is a local community action group dedicated to improving the lives of those who live and work in Middleport and the surrounding areas.

title: Middleport, Staffordshire


text:
Wikipedia:Articles for deletion/Geobeecentral

Geobeecentral was proposed for deletion. This page is an archive of the discussion about the proposed deletion. This page is no longer live. Further comments should be made on the article's talk page rather than here so that this page is preserved as an historic record. The result of the debate was DELETE

It's a web site. It's new and not particularly popular, according to this article. I don't see any evidence of notability, but I do see advertising. Cdc 01:19, 20 Dec 2004 (UTC)

 * Delete. It's too new.  If it's still around in 10 years, and popular, then maybe an article.  But we don't need an article about every web site on Earth. --Dbenbenn 01:43, 20 Dec 2004 (UTC)
 * Delete  --fvw *  08:22, 2004 Dec 20 (UTC)
 * Delete: DCEdwards1966 20:48, Dec 20, 2004 (UTC)
 * Delete, ad, nn (yet). Wyss 00:33, 21 Dec 2004 (UTC)
 * Delete. Ad. utcursch 07:28, Dec 21, 2004 (UTC)
 * Delete Trivial @best. User:netkinetic

This page is now preserved as an archive of the debate and, like some other VfD subpages, is no longer 'live'. Subsequent comments on the issue, the deletion or on the decision-making process should be placed on the relevant 'live' pages. Please do not edit this page.


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Gaekwad dynasty

Gaekwads (also spelled as Gaikwads, Guicowars, Gaekwars) (IAST: Gāyakavāḍa), a Hindu Maratha dynasty of the former Maratha Confederacy and its subsequent (erstwhile) princely state of Baroda in western India from the early 18th century until 1947. The ruling prince was known as the Maharaja Gaekwad of Baroda. With the city of Baroda (Vadodara) as its capital, during the British Raj its relations with the British were managed by the Baroda Residency. It was one of the largest and wealthiest princely states existing alongside British India, with wealth coming from the lucrative cotton business as well as rice, wheat and sugar production.

Early history
The Gaekwad rule of Baroda began when the Maratha general Pilaji Rao Gaekwad conquered the city from the Mughal Empire in 1721. The Gaekwads were granted the city as a Jagir by Chhatrapati Shahu I, the Chhatrapati of the Maratha empire.

In their early years, the Gaekwads served as subordinates of the Dabhade family, who were the Maratha chiefs of Gujarat and holders of the senapati (commander-in-chief) title. When Umabai Dabhade joined Tarabai's side against Balaji Baji Rao, Pilaji's son Damaji Rao Gaekwad commanded the Dabhade force. He was defeated, and remained under Peshwa's arrest from May 1751 to March 1752. In 1752, he was released after agreeing to abandon the Dabhades and accept the Peshwa's suzerainty. In return, Damaji was made the Maratha chief of Gujarat, and the Peshwa helped him expel the Mughals from Gujarat.

Damaji subsequently fought alongside Sadashiv Rao, Vishwas Rao, Malhar Rao Holkar, Jankoji Scindia, Sidhoji Gharge-Desai (Deshmukh) and Mahadji Shinde in the Third Battle of Panipat (1761). After the Maratha defeat at Panipat, the central rule of the Peshwas was weakened. As a result, the Gaekwads, along with several other powerful Maratha clans, established themselves as virtually independent rulers, while recognizing the nominal authority of the Peshwas and suzerainty of the Bhonsle Maharaja of Satara.

British suzerainty
The Gaekwads, together with several Maratha chieftains, fought the British in the First Anglo-Maratha War.

On 15 March 1802, the British intervened to defend the Gaekwad Maharaja, Anand Rao Gaekwad, who had recently inherited the throne against rival claimants, and the Gaekwads concluded the Treaty of Cambey with the British that recognized their independence from the Maratha empire and guaranteed the Maharajas of Baroda local autonomy in return for recognizing British suzerainty.

Maharaja Sayaji Rao III, who took the throne in 1875, did much to modernize Baroda, establishing compulsory primary education, a library system and the Maharaja Sayajirao University of Baroda. He also encouraged the setting up of textile factories, which helped create Baroda's textile industry. He is well known for offering B. R. Ambedkar a scholarship to study at Columbia University.

Upon India attaining its independence in 1947, the last ruling Maharaja of Baroda, Pratapsinhrao, acceded to India. Baroda was eventually merged with Bombay State, which was later divided, based on linguistic principle, into the states of Gujarat and Maharashtra in 1960.

Gaekwad or Gayakwad also survives as a fairly common Maratha surname, found mainly in the Indian state of Maharashtra.

Gaikwad Maharajas of Baroda

 * Nandaji Rao Gaikwad, died May 1721
 * Kerojirao
 * Jhingojirao
 * Pilaji Rao Gaikwad, reigned from 1721, died 14 May 1732
 * [[Image:Simple silver crown.svg|15px]] I. Damaji Rao, reigned from 1732, died 18 August 1768
 * [[Image:Simple silver crown.svg|15px]] II. Sayaji Rao I, reigned 1768–1778, died 1792
 * [[Image:Simple silver crown.svg|15px]] III. Fateh Singh Rao I, born before April 1751, reigned from 1778, died 26 December 1789
 * [[Image:Simple silver crown.svg|15px]] IV. Manaji Rao, born before April 1751, reigned from 1789, died 27 July 1793
 * [[Image:Simple silver crown.svg|15px]] V. Govind Rao, born 175?, reigned from 1793, died 19 September 1800
 * [[Image:Simple silver crown.svg|15px]] VI. Anand Rao, born 179?, reigned from 1800, died 2 October 1819
 * [[Image:Simple silver crown.svg|15px]] VI. Sayajirao II, born 3 May 1800, reigned from 1819, died 28 December 1847
 * [[Image:Simple silver crown.svg|15px]] VII. Ganpat Rao, born 1816, reigned from 1847, died 1856
 * [[Image:Simple silver crown.svg|15px]] VIII. Khanderao II GCSI, born 1828, reigned from 1856, died 14 June 1870
 * [[Image:Simple silver crown.svg|15px]] IX. Malhar Rao, born 1831, reigned 1870 – 19 April 1875, died in obscurity in 1882
 * Prataprao (d. 1737 Kavlana branch)
 * Kalojirao
 * Gabajirao
 * Bhikajirao
 * Kashirao (1832-1877)
 * [[Image:Simple silver crown.svg|15px]] X. Sayajirao III GCSI, GCIE, born 10 March 1863, reigned from 1875, died 6 February 1939
 * Yuvraja Fatehsinhrao (1883-1908)
 * [[Image:Simple silver crown.svg|15px]] XI. Pratap Singh Rao GCIE, born 29 June 1908, reigned from 1939, titular Maharaja from 1949, deposed 1951, died 19 July 1968
 * [[Image:Simple silver crown.svg|15px]] XII. Fatehsinhrao II, born 2 April 1930, titular Maharaja 1951–1971, family head: 1971–1988, died 1 September 1988
 * XIII. Ranjitsinh, born 8 May 1938, family head from 1988, died 9 May 2012
 * XIV. Samarjitsinh, born 25 April 1967, family head since 2012

title: Gaekwad dynasty


text: User talk:151.199.31.138

title: User talk:151.199.31.138


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Talk:Harvard Business School

A Commons file used on this page or its Wikidata item has been nominated for deletion
The following Wikimedia Commons file used on this page or its Wikidata item has been nominated for deletion: Participate in the deletion discussion at the. —Community Tech bot (talk) 00:08, 1 March 2023 (UTC)
 * Inside a Harvard Business School classroom.jpeg

title: Talk:Harvard Business School


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Shangrao

Shangrao is a medium-sized prefecture-level city located in the northeast of Jiangxi province, People's Republic of China. The city borders the province of Anhui to the north, the province of Zhejiang to the east, and the province of Fujian to the south. Also, the city's western reaches extend into Poyang Lake. Shangrao had a population of 6,491,088 as of 2020 census whom 1,293,399 lived in the built up (or metro) area made of Xinzhou and Guangxin districts, Guangfeng District not being conurbated yet. Shangrao itself is at the very western edge of the Wu-speaking areas, while most of its associated counties speak Gan.

Subdivisions
Shangrao administers three districts, one county-level city, and eight counties. The information here presented uses data from 2010 national census.

Railway
Shangrao Railway Station is served by three major railways passing through Shangrao: the Shanghai–Kunming Railway, the Shanghai–Kunming High-Speed Railway and the Hefei–Fuzhou High-Speed Railway.

Air
Shangrao Sanqingshan Airport opened on 28 May 2017.

Education

 * Shangrao Normal University (上饶师范学院) is located in Shangrao. It was originally named Shangrao Normal Junior College when it was founded in 1958, and changed its name to Gan Dongbei (Northeastern part of Jiangxi) University in 1959. It was closed down during the period of the Chinese Cultural Revolution. Authorized by the State Council, Shangrao Normal Junior College was restored in 1977. Then, with authorization of Ministry of Education and People's Government of Jiangxi Province, it changed its name to Shangrao Normal College in March 2000. Over the past 20 years, more than 26,000 students graduated from Shangrao Normal University, to work in various careers in China.

Sports
The 21,000-capacity Shangrao Stadium is located in the city. It is used mostly for football matches.

title: Shangrao


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Industrial district

Industrial district (ID) is a place where workers and firms, specialised in a main industry and auxiliary industries, live and work. The concept was initially used by Alfred Marshall to describe some aspects of the industrial organisation of nations. At the end of the 1990s the industrial districts in developed or developing countries had gained a recognised attention in international debates on industrialisation and policies of regional development.

History of the term
The term was used the first time by Alfred Marshall in The Principles of Economics (1890, 1922) and in his Industry and Trade Marshall talks of a.... "thickly peopled industrial district".

The term was also used in political struggle. The 1917 handbook of the Industrial Workers of the World states:-

 * "In order that every given industrial district shall have complete industrial solidarity among the workers in all industries as well as among the workers of each an INDUSTRIAL DISTRICT COUNCIL is formed ..."

The term also appears in English literature. For instance, in a short story of 1920 by D. H. Lawrence, You Touched Me (aka 'Hadrian'):-

 * "Matilda and Emmie were already old maids. In a thorough industrial district, it is not easy for the girls who have expectations above the common to find husbands. The ugly industrial town was full of men, young men who were ready to marry. But they were all colliers or pottery-hands, mere workmen."

The strong specialisation of the workers and an appropriate support of public goods and institutions are supported by an "Industrial Atmosphere" related to a locally developing division of labour. Competences and knowledge are shared in informal way with processes of learning by doing and learning by using, and this promotes innovation over time. Local firms, families and civic organisations are connected by way of both market mechanisms and non-market mechanisms, like trust within bilateral or team exchanges, and collective action supporting the availability of local industrial, social and environmental infrastructure. Also, the notion that firms located in geographical proximity benefit from agglomeration effects in having a common or collective infrastructure is frequently mentioned as one of the main bases in the industrial district literature.

Recent evolution of the use of the term
Within the study of economics, the term has evolved. Giacomo Becattini rediscovered the concept to describe the Italian industrial configuration of the middle of the 20th century. Since the 1980s, the dynamic industrial development in NEC (North, East and Centre) of Italy, where after the Second World War geographical concentration of specialised small and medium-sized enterprises (SME) raised up, led to an increasing attention to the Marshall' seminal works. A growing literature with an accompanying cloud of definitions of what is meant as an industrial district characterised the international dabate, e.g. Cluster. Industrial districts in Italy have a coherent location and a narrow specialisation profile, e.g. Prato in woollen fabric, Sassuolo in ceramic tiles or Brenta in ladies' footwear.

The success of SME-based Italian districts in the last century and the alternate fortunes of the current ones led to investigate more thoroughly some related aspects. The general characteristics of the ID are consistent with gradual change supported by processes of innovation from below, or decentralized industrial creativity. However, the globalisation processes asked non-gradual changes to the historical IDs and technical and organisational difficulties could hit them.

In the Industry 4.0 era, the specialised capabilities of these areas seem to have the possibility to encourage the emergence of the New Artisans, Maker in the context of adapted models like the "ID mark 3.0".

title: Industrial district


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Talk:Line doubler

Untitled
Shouldn't this article link back to the deinterlace article? ABostrom 01:26, 2004 Dec 20 (UTC)

I would argue that this page is not correct. Line doubling and de-interlacing are not the same thing. A line doubler, as the name suggests, would be something that simply duplicates each line. This is what a VGA video card does when displaying a 200 line CGA-compatible mode for instance (because VGA monitors were designed to run at a 31KHz line rate and are generally incapable of running at the lower 15KHz scanrate used by a real CGA card). The purpose is to modify one progressive scan data stream to be displayed on higher resolution display. De-interlacing is different and more complicated, as the goal is to combine consecutive fields into one full-resolution frame. This requires buffering at least an entire field, if not a whole frame. It may also include filters to work around the artifacts resulting from the fields in the original stream being sampled at different times (commonly the case with SDTV signals).69.205.239.137 (talk) 08:08, 8 August 2008 (UTC)

 * I guess so but this one i can think deinterlacers like this which is linear deinterlacer and converts that framerate up and have smooth progressive playback.--HappyLogolover2011 (talk) 23:37, 10 April 2011 (UTC)

title: Talk:Line doubler


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Karnaphuli

The Karnaphuli River (কর্ণফুলি Kôrnophuli; also spelt Karnafuli and Khawthlangtuipui in Mizo, meaning "western river" and Borgang in Chakma, meaning "Big River") is the largest and most important river in Chittagong and the Chittagong Hill Tracts. It is a 667 m wide river in the south-eastern part of Bangladesh. Originating from the Saithah village of Mamit district in Mizoram, India, it flows 270 km southwest through Chattogram Hill Tracts and Chattogram into the Bay of Bengal. It is the fastest flowing river in Bangladesh, after the Padma. It is said to "represent the drainage system of the whole south-western part of Mizoram." Principal tributaries include the Kawrpui River or Thega River, Tuichawng River and Phairuang River. A large hydroelectric power plant was built on the Karnaphuli in the Kaptai region in the 1960s. The mouth of the river hosts the Port of Chattogram, the largest and busiest seaport of Bangladesh.

Etymology
The presence of Arab traders and merchants in the history of Chittagong led to many areas in Chittagong to have names of Arabic origin. The name of this river is thought to have come from qarnaful, the Arabic word for clove, and refers to an incident in which an Arab ship full of cloves sank in this river.

Chittagong City
Chittagong is situated on the banks of the Karnaphuli River between the Chittagong Hill Tracts and the Bay of Bengal. The city is a noteworthy seaside seaport city and monetary focus in southeastern Bangladesh. The Chittagong Metropolitan Area has a populace of more than 8.9 million, making it the second biggest city in Bangladesh. It is the capital of an eponymous locale and division. A water treatment plant has been set up by Chittagong Port Authority to source water from the Karnaphuli river for its uses. The plant will make the port self-reliant in its water needs.

Tlabung
Tlabung is situated on the banks of the Karnaphuli River in Lunglei district, Mizoram. Karnaphuli River links Mizoram with the port cit of Chittagong on the shores of Bay of Bengal. British Troops and missionaries used this route to reach Mizoram during the Colonial days. It used to take 5 days to reach from Chittagong to Tlabung on a motorboat, a distance of about 90 kilometers after which they would travel another 35 kilometers to reach Lunglei.

Transportation
The Government has awarded a contract to build a two lane Karnaphuli tunnel underneath the Karnaphuli river to China Communication Construction Company (CCCC). This will be the first underwater tunnel in Bangladesh. CCCC will receive $706 million for its services with total costs expected to be over $1 billion.

Aquatic life
The river is home to Ganges river dolphin, which is an endangered species. Hilsa used to be common in the river, but have nearly disappeared from the river due to pollution.

Kaptai dam
The Kaptai Dam is the location of the Karnafuli Hydroelectric Power Station, constructed in Kaptai in 1962 and the only hydro-electric power plant in the country. An earth-filled dam on the Karnaphuli River, the Kaptai Dam created the Kaptai Lake, which acts as the water reservoir for the hydropower station. The power plant produces a total of 230 megawatts of electricity. When then east Pakistan built the dam, Indian Prime Minister Jawaharlal Nehru didn't object even though it resulted in part of Indian side getting submerged and inflow of more than 40000 refugees.

Pollution
Like many rivers in Bangladesh, Karnaphuli is heavily polluted by agricultural runoff. Reducing the amount of oxygen available and harming aquatic life in the river. In 2015, a train carrying oil crashed over a tributary of the river. The spill caused environmental degradation.

title: Karnaphuli


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Wikipedia talk:Reviewing mediation

Ack - I'd missed this page. I think it's about time we gave some serious thought to what is and isn't working, and I think this is a pretty good step.

As another one of the outgoing mediators, I've also got a few suggestions.

I think it would help if we had a concrete mailing list, rather than having to grab everyone's email addresses each time we want to get in touch, particularly now that the boards are dead. I think this'd see a few more of the mediators keep up with things. It may be worth creating an IRC channel as well. In this way, I think sannse's idea of working as a committee more often, instead of always as individuals, would be a wise move.

I think we should be keeping a much tighter ship. If someone makes a request for mediation, then IMHO, we should be getting in touch with the other party within hours, and then getting in touch with a mediators mailing list as soon as the other party consents. As part of this, I think it would help to reduce the chair terms to one month, and appoint them by simply sending out a message asking who wants to do it, and who has the most time, rather than the present system, which is a little disorganised. I think it's this which is leading to us getting bypassed in favour of arbitration.

I think it would help - a lot - if some of us who aren't quite so good could gain guidance from some of those who are, such as Ed. I wonder if it would be possible to put together some sort of "Mediation Manual", so that the likes of Ed could share their knowledge with the newcomers. In this way, I'm quite glad that Ed isn't one of the people leaving the Committee.

I'm a little wary about the idea of "mediation with teeth", as I'm inclined to think that on the few occasions where mediators have reported to the arbitration committee along the lines of "X has cooperated, but Y hasn't", the cases concerned have more often than not been bad-faith ones. I really don't think this is necessary anyway - as long as we're prompt, organised and skilled, then arbitration can deal with the leftovers.

Finally, I think we should be putting out a request - preferably today - for new mediators, advertised in all the usual places. We're losing four mediators, which is a significant proportion of our active people. Thankfully we've still got Ed, but it's not very good if he's doing the whole workload. Ambi 01:27, 20 Dec 2004 (UTC)

Here are my thoughts:
 * Users ought to try WP:RFC first. This would filter out the pointless cases.
 * The Requests for mediation page should not be used for ranting. Users should not make their arguments until they are in mediation. Having continual fights on that page does not make it easy to see what the current status of the cases are, and only imflames the situation.
 * Mediation should be done by the mediation committee as a whole or by groups of mediators, not by an individual mediator. This would make it more fun, less stressful, and hopefully would make things proceed more quickly.
 * We need more guidance on when to close a case and more power to do something other than just listen to people complaining about each other.

Angela. 06:28, Jan 29, 2005 (UTC)

scarcity of mediators
I have just started mediating and I have not noticed a scarcity of mediators. I think people are signing up to be mediators and the current lag is only a few days. Maybe this will change later but for now it seems ok.

I would say one problem is mediators who do not have enough time to do a "hands-on" mediation and respond quickly to issues. This could be addressed by assigning multiple mediators to each case; this seems to have worked well on the cases where I have seen it. Ideogram 18:07, 21 June 2006 (UTC)

title: Wikipedia talk:Reviewing mediation