title: Allosteric regulation

text: A non-regulatory allosteric site is any non-regulatory component of an enzyme (or any protein), that is not itself an amino acid. For instance, many enzymes require sodium binding to ensure proper function. However, the sodium does not necessarily act as a regulatory subunit; the sodium is always present and there are no known biological processes to add/remove sodium to regulate enzyme activity. Non-regulatory allostery could comprise any other ions besides sodium (calcium, magnesium, zinc), as well as other chemicals and possibly vitamins.


title: Allosteric regulation

text: Allosteric modulation of a receptor results from the binding of allosteric modulators at a different site (a "regulatory site") from that of the endogenous ligand (an "active site") and enhances or inhibits the effects of the endogenous ligand. Under normal circumstances, it acts by causing a conformational change in a receptor molecule, which results in a change in the binding affinity of the ligand. In this way, an allosteric ligand modulates the receptor's activation by its primary orthosteric ligand, and can be thought to act like a dimmer switch in an electrical circuit, adjusting the intensity of the response.


title: Allosteric regulation

text: For example, the GABA receptor has two active sites that the neurotransmitter gamma-aminobutyric acid (GABA) binds, but also has benzodiazepine and general anaesthetic agent regulatory binding sites. These regulatory sites can each produce positive allosteric modulation, potentiating the activity of GABA. Diazepam is a positive allosteric modulator at the benzodiazepine regulatory site, and its antidote flumazenil is an receptor antagonist.


title: Allosteric regulation

text: More recent examples of drugs that allosterically modulate their targets include the calcium-mimicking cinacalcet and the HIV treatment maraviroc.


title: Allosteric regulation

text: Allosteric sites may represent a novel . There are a number of advantages in using allosteric modulators as preferred therapeutic agents over classic orthosteric ligands. For example, G protein-coupled receptor (GPCR) allosteric binding sites have not faced the same evolutionary pressure as orthosteric sites to accommodate an endogenous ligand, so are more diverse. Therefore, greater GPCR selectivity may be obtained by targeting allosteric sites. This is particularly useful for GPCRs where selective orthosteric therapy has been difficult because of sequence conservation of the orthosteric site across receptor subtypes. Also, these modulators have a decreased potential for toxic effects, since modulators with limited co-operativity will have a ceiling level to their effect, irrespective of the administered dose. Another type of pharmacological selectivity that is unique to allosteric modulators is based on co-operativity. An allosteric modulator may display neutral co-operativity with an orthosteric ligand at all subtypes of a given receptor except the subtype of interest, which is termed "absolute subtype selectivity". If an allosteric modulator does not possess appreciable efficacy, it can provide another powerful therapeutic advantage over orthosteric ligands, namely the ability to selectively tune up or down tissue responses only when the endogenous agonist is present. Oligomer-specific small molecule binding sites are drug targets for medically relevant morpheeins.


title: Allosteric regulation

text: There are many synthetic compounds containing several noncovalent binding sites, which exhibit conformational changes upon occupation of one site. Cooperativity between single binding contributions in such supramolecular systems is positive if occupation of one binding site enhances the affinity Δ"G" at a second site, and negative if the affinity isn't highered. Most synthetic allosteric complexes rely on conformational reorganization upon the binding of one effector ligand which then leads to either enhanced or weakened association of second ligand at another binding site. Conformational coupling between several binding sites is in artificial systems usually much larger than in proteins with their usually larger flexibility. The parameter which determines the efficiency (as measured by the ratio of equilibrium constants Krel = KA(E)/KA in presence and absence of an effector E ) is the conformational energy needed to adopt a closed or strained conformation for the binding of a ligand A.


title: Allosteric regulation

text: In many multivalent supramolecular systems direct interaction between bound ligands can occur, which can lead to large cooperativities. Most common is such a direct interaction between ions in receptors for ion-pairs. This cooperatitiy is often also referred to as allostery, even though conformational changes here are not necessarily triggering binding events.


title: Allosteric regulation

text: Allostery is a direct and efficient means for regulation of biological macromolecule function, produced by the binding of a ligand at an allosteric site topographically distinct from the orthosteric site. Due to the often high receptor selectivity and lower target-based toxicity, allosteric regulation is also expected to play an increasing role in drug discovery and bioengineering. The AlloSteric Database (ASD) provides a central resource for the display, search and analysis of the structure, function and related annotation for allosteric molecules. Currently, ASD contains allosteric proteins from more than 100 species and modulators in three categories (activators, inhibitors, and regulators). Each protein is annotated with detailed description of allostery, biological process and related diseases, and each modulator with binding affinity, physicochemical properties and therapeutic area. Integrating the information of allosteric proteins in ASD should allow the prediction of allostery for unknown proteins, to be followed with experimental validation. In addition, modulators curated in ASD can be used to investigate potential allosteric targets for a query compound, and can help chemists to implement structure modifications for novel allosteric drug design.


title: Allosteric regulation

text: Not all protein residues play equally important roles in allosteric regulation. The identification of residues that are essential to allostery (so-called “allosteric residues”) has been the focus of many studies, especially within the last decade. In part, this growing interest is a result of their general importance in protein science, but also because allosteric residues may be exploited in biomedical contexts. Pharmacologically important proteins with difficult-to-target sites may yield to approaches in which one alternatively targets easier-to-reach residues that are capable of allosterically regulating the primary site of interest. These residues can broadly be classified as surface- and interior-allosteric amino acids. Allosteric sites at the surface generally play regulatory roles that are fundamentally distinct from those within the interior; surface residues may serve as receptors or effector sites in allosteric signal transmission, whereas those within the interior may act to transmit such signals.


title: Erythromelalgia

text: Erythromelalgia or Mitchell's disease (after Silas Weir Mitchell) is a rare vascular peripheral pain disorder in which blood vessels, usually in the lower extremities or hands, are episodically blocked (frequently on and off daily), then become hyperemic and inflamed. There is severe burning pain (in the small fiber sensory nerves) and skin redness. The attacks are periodic and are commonly triggered by heat, pressure, mild activity, exertion, insomnia or stress. Erythromelalgia may occur either as a primary or secondary disorder (i.e. a disorder in and of itself or a symptom of another condition). Secondary erythromelalgia can result from small fiber peripheral neuropathy of any cause, polycythemia vera, essential thrombocytosis, hypercholesterolemia, mushroom or mercury poisoning, and some autoimmune disorders. Primary erythromelalgia is caused by mutation of the voltage-gated sodium channel α-subunit gene "SCN9A".


title: Erythromelalgia

text: In 2004 erythromelalgia became the first human disorder in which it has been possible to associate an ion channel mutation with chronic neuropathic pain, when its link to the SCN9A gene was initially published in the "Journal of Medical Genetics". Later that year, in an article in "The Journal of Neuroscience", Cummins et al., demonstrated, using voltage clamp recordings, that these mutations enhanced the function of Na1.7 sodium channels, which are preferentially expressed within peripheral neurons. One year later, in an article in "Brain", Dib-Hajj et al., demonstrated that Na1.7 mutants channels, from families with inherited erythromelalgia (IEM), make dorsal root ganglion (DRG, peripheral and sensory), neurons hyper excitable, thereby demonstrating the mechanistic link between these mutations and pain, thereby firmly establishing Na1.7 gain-of-function mutations as the molecular basis for IEM. Conversely, in December 2006 a University of Cambridge team reported an SCN9A mutation that resulted in a complete lack of pain sensation in a Pakistani street performer and some of his family members. He felt no pain, walked on hot coals and stabbed himself to entertain crowds. By 2013, nearly a dozen gain-of-function mutations of Na1.7 had been linked to IEM. The multi-decades search which identified gene SCN9A as the cause of inherited erythomelalgia is documented in a book by Stephen Waxman, "Chasing Men on Fire: The Story of the Search for a Pain Gene".


title: Erythromelalgia

text: Primary erythromelalgia may be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Both of these may be further classified as either juvenile or adult onset. The juvenile onset form occurs prior to age 20 and frequently prior to age 10. While the genetic cause of the juvenile and sporadic adult onset forms is often known, this is not the case for the adult onset familial form.


title: Erythromelalgia

text: In rural areas of southern China, outbreaks of erythromelalgia have occurred during winter and spring at 3-5 year intervals among secondary school students. This epidemic form of erythromelalgia has been viewed as a different form of non-inherited primary erythromelalgia and affects mainly teenage girls in middle schools. The disease is characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients may have fever, palpitations, headache, and joint pain. In the 1987 epidemic in Hubei, 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis.


title: Erythromelalgia

text: Erythromelalgia can be found in several billing codes systems and other systems. Erythromelalgia is generally classified as a disease of the circulatory system, falling under the class of "other peripheral vascular disease", as the following two billing code systems will show:


title: Erythromelalgia

text: The most prominent symptoms of erythromelalgia are episodes of erythema, swelling, a painful deep-aching of the soft tissue (usually either radiating or shooting) and tenderness, along with a painful burning sensation primarily in the extremities. These symptoms are often symmetric and affect the lower extremities more frequently than the upper extremities. Symptoms may also affect the ears and face. For secondary erythromelalgia, attacks typically precede and are precipitated by the underlying primary condition. For primary erythromelalgia, attacks can last from an hour to months at a time and occur infrequently to frequently with multiple times daily. Attacks most frequently occur at night, thus having the potential to greatly interfere with sleep. Common triggers for daytime episodes are exertion, heating of the affected extremities, and alcohol or caffeine consumption, and any pressure applied to the limbs. In some patients sugar and even melon consumption have also been known to provoke attacks. Many of those with primary erythromelalgia avoid wearing shoes or socks as the heat this generates is known to produce erythromelalgia attacks. The coexistence of erythromelalgia and Raynaud's phenomenon is rare, but case studies of patients with both diagnoses have been reported in medical journals. Symptoms may present gradually and incrementally, sometimes taking years to become intense enough for patients to seek medical care. In other cases symptoms emerge full blown with onset.


title: Erythromelalgia

text: Epidemic erythromelalgia is characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients may have fever, palpitations, headache, and joint pain. In the 1987 epidemic in Hubei, 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis.


title: Erythromelalgia

text: In general, erythromelalgia seems to consist of neuropathological and microvascular alterations. How this occurs in secondary erythromelalgia is poorly understood and may be specific to the underlying primary condition. Primary conditions that have been shown to elicit erythromelalgia are listed in diagnosis, below.


title: Erythromelalgia

text: Primary erythromelalgia is a better understood autosomal dominant disorder. The neuropathological symptoms of primary erythromelalgia arise from hyperexcitability of C-fibers in the dorsal root ganglion. Specifically, nociceptors (neurons responsible for the sensation and conduction of painful stimuli) appear to be the primarily affected neurons in these fibers. This hyperexcitability results in the severe burning pain experienced by patients. While the neuropathological symptoms are a result of hyperexcitability, microvascular alterations in erythromelalgia are due to hypoexcitability. The sympathetic nervous system controls cutaneous vascular tone and altered response of this system to stimuli such as heat likely results in the observed microvascular symptoms. In both cases, these changes in excitability are typically due to mutation of the sodium channel Na1.7. These differences in excitability alterations between the sympathetic nervous system and nociceptors is due to different expression of sodium channels other than Na1.7 in them.


title: Erythromelalgia

text: What causes epidemic erythromelalgia in southern China remains unknown although several erythromelalgia-associated poxviruses were isolated from throat swabs of several patients at different counties and from two different seasons.


title: Erythromelalgia

text: Several medications, including verapamil and nifedipine, as well as ergot derivatives such as bromocriptine and pergolide, have been associated with medication-induced erythromelalgia.


title: Erythromelalgia

text: The consumption of two species of related fungi, "Clitocybe acromelalga" from Japan, and "Clitocybe amoenolens" from France, has led to several cases of mushroom-induced erythromelalgia which lasted from 8 days to 5 months.


title: Erythromelalgia

text: An epidemic form of this syndrome occurs in secondary school students in rural areas of China. A large epidemic erythromelalgia was occurred in Hubei province of China in 1987 and the disease was characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients had fever, palpitations, headache, and joint pain. 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. Subsequently, a virus - erythromelalgia-related poxvirus (ERPV) - was repeatedly isolated from throat swabs of six separate patients from two different counties and Wuhan city in Hubei province. The genome of this virus has been sequenced and it appears that this virus is related to a strain of mousepox. Serological characterization can easily distinguish human ERPV from ectromelia virus and vaccinia virus by cross-neutralization and plaque reduction assays


title: Erythromelalgia

text: Since this virus has not yet been isolated from other outbreaks in other parts of southern China to date this putative association needs to be further investigated. The finding of the specific antibody conversion to ATIs of ERPV in patients' paired sera strengthens the evidence for a possible aetiological role of human ERPV in epidemic erythromelalgia.


title: Erythromelalgia

text: There are 10 known mutations in the voltage-gated sodium channel α-subunit Na1.7 encoding gene, "SCN9A". This channel is expressed primarily in nociceptors of the dorsal root ganglion and the sympathetic ganglion neurons. Nine of these mutations have received further study and they have all shown to result in similar biophysical alterations, Table 1. As can be seen from table 1, the primary effect of erythromelalgia mutations is Na1.7 channels that activate at more hyperpolarized potentials. Na1.7 channels act largely as threshold sensors and initiate action potentials. Consequently, this shift in their activation profile results in channels that open closer to the resting membrane potential. In many mutations, this shift of activation is accompanied by shifts in the voltage sensitivity of fast and/or slow inactivation, often in the depolarized direction. This results in channels that are open for a longer of period of time, producing larger and more prolonged changes in membrane potential.


title: Erythromelalgia

text: Some of these mutant channels have been expressed in dorsal root ganglion (DRG) or sympathetic neurons. In DRG neurons expressing the F1449V mutation, a lower threshold is required for action potential creation (93.1 ± 12.0 pA) than those expressing wild-type channels (124.1 ± 7.4 pA). Furthermore, while DRG neurons expressing wild-type channels only respond with a few action potentials, those expressing F1449V channels respond with a high-frequency train of action potentials. There is a similar effect in DRG neurons expressing the L858H and A863P mutants. Here, there is also a notable change in resting membrane potential, being depolarized by 4-7 mV versus wild-type channel expressing cells. The situation is different, however, in sympathetic neurons expressing the L858H mutation. While L858H expressing sympathetic ganglion are depolarized ~5mV relative to wild-type expressing neurons, their threshold for action potential initiation is notably higher. Furthermore, while current injection of 40pA for 950ms provokes an average of 6 action potentials in sympathetic neurons expressing wild-type channels this stimulation evokes only approximately 2 action potentials with reduced overshoots in sympathetic neurons expressing L858H mutant channels. Further investigation has demonstrated that the differences in response between DRG and sympathetic neurons is due to expression of Na1.8 in the former. Consequently, expression of Na1.8 channels in sympathetic neurons also expressing L858H mutant Na1.7 results in neurons with a depolarized resting membrane potential that nevertheless have a normal action potential threshold and overshoot.


title: Erythromelalgia

text: An effective, though not recommended, treatment for erythromelalgia symptoms is cooling of the affected area. Activation of wild-type channels is unaffected by cooling. L858F mutant channels, however, are activated at more depolarized potentials when cooled than at normal body temperature. At 16 °C the activation V of the mutant channel is only 4.6mV more hyperpolarized that wild-type versus 9.6mV more hyperpolarized at 35 °C. Fast inactivation is affected in a similar manner in both wild-type and L858F mutant channel and is, thus, unlikely to contribute to symptom resolution due to cooling. While such cooling is unlikely to affect neuronal cell bodies, axons and termini express Na1.7 and are present in the skin.


title: Erythromelalgia

text: Erythromelalgia is a difficult condition to diagnose as there are no specific tests available. However, reduced capillary density has been observed microscopically during flaring; and reduced capillary perfusion is noted in the patient. Another test that can be done is to have the patient elevate their legs, and note the reversal (from red to pale) in skin color. Tests done at universities include quantitative sensory nerve testing, laser evoked potentials, sweat testing and epidermal sensory nerve fiber density test (which is an objective test for small fiber sensory neuropathy). Due to the aforementioned factors, patients may face delays in diagnosis.


title: Erythromelalgia

text: Once it has been established that it is not secondary erythromelalgia — see below — a programme of management can be put in place.Some diseases present with symptoms similar to erythromelalgia. Complex regional pain syndrome (CRPS), for instance, presents with severe burning pain and redness except these symptoms are often unilateral (versus symmetric) and may be proximal instead of purely or primarily distal. Furthermore, attacks triggered by heat and resolved by cooling are less common with CRPS.


title: Erythromelalgia

text: Erythromelalgia is sometimes caused by other disorders. A partial list of diseases known to precipitate erythromelalgia is below.


title: Erythromelalgia

text: For secondary erythromelalgia, treatment of the underlying primary disorder is the most primary method of treatment. Although aspirin has been thought to reduce symptoms of erythromelalgia, it is rare to find evidence that this is effective. Mechanical cooling of the limbs by elevating them can help or managing the ambient environment frequently is often necessary constantly as flares occur due to sympathetic autonomic dysfunction of the capillaries. The pain that accompanies it is severe and treated separately (the pain is similar to CRPS, phantom limb or thalamic pain syndrome). Patients are strongly advised "not" to place the affected limbs in cold water to relieve symptoms when flaring occurs. It may seem a good idea, but it precipitates problems further down the line causing damage to the skin and ulceration often intractable due to the damaged skin. A possible reduction in skin damage may be accomplished by enclosing the flaring limb in a commonly available, thin, heat transparent, water impermeable, plastic food storage bag. The advice of a physician is advised depending on specific circumstances.


title: Erythromelalgia

text: Primary erythromelalgia management is symptomatic, i.e. treating painful symptoms only. Specific management tactics include avoidance of attack triggers such as: heat, change in temperature, exercise or over exertion, alcohol and spicy foods. This list is by no means comprehensive as there are many triggers to set off a 'flaring' episode that are inexplicable. Whilst a cool environment is helpful in keeping the symptoms in control, the use of cold water baths is strongly discouraged. In pursuit of added relief sufferers can inadvertently cause tissue damage or death, i.e. necrosis. See comments at the end of the preceding paragraph regarding possible effectiveness of plastic food storage bags to avoid/reduce negative effects of submersion in cold water baths.


title: Erythromelalgia

text: One clinical study has demonstrated the efficacy of IV lidocaine or oral mexilitine, though differences between the primary and secondary forms were not studied. Another trial has shown promise for misoprostol, while other have shown that gabapentin, venlafaxine and oral magnesium may also be effective, but no further testing was carried out as newer research superseded this combination.


title: Erythromelalgia

text: Strong anecdotal evidence from EM patients shows that a combination of drugs such as duloxetine and pregabalin is an effective way of reducing the stabbing pains and burning sensation symptoms of erythromelalgia in conjunction with the appropriate analgesia. In some cases, antihistamines may give some relief. Most people with erythromelalgia never go into remission and the symptoms are ever present at some level, whilst others get worse, or the EM is eventually a symptom of another disease such as systemic scleroderma.


title: Erythromelalgia

text: Some suffering with EM are prescribed ketamine topical creams as a way of managing pain on a long-term basis. Feedback from some EM patients has led to reduction in usage as they believe it is only effective for short periods.Living with erythromelalgia can result in a deterioration in quality of life resulting in the inability to function in a work place, lack of mobility, depression, and is socially alienating; much greater education of medical practitioners is needed. As with many rare diseases, many people with EM end up taking years to get a diagnosis and to receive appropriate treatment.Research into the genetic mutations continues but there is a paucity of clinical studies focusing on living with erythromelalgia. There is much urgency within pharmaceutical companies to provide a solution to those who suffer with pain such as that with erythromelalgia.


title: Erythromelalgia

text: Patients find relief by cooling the skin. All patients must be notified to not apply ice directly on to the skin, since this can cause maceration of the skin, nonhealing ulcers, infection, necrosis, and even amputation in severe cases.


title: Erythromelalgia

text: Mild sufferers may find sufficient pain relief with tramadol or amitriptyline. Sufferers of more severe and widespread EM symptoms, however, may obtain relief only from opioid drugs. Opana ER has been found to be effective for many in the US, whilst in the UK slow-release morphine has proved to be effective. These powerful and potentially-addictive drugs may be prescribed to patients only after they have tried almost every other type of analgesia to no avail. (This delay in appropriate pain management can be a result of insurer-mandated or legally-required step therapy, or merely overly-cautious prescribing on the part of sufferers' doctors.)


title: Erythromelalgia

text: The combination of Cymbalta (duloxetine) and Lyrica (pregabalin) has also proven to be useful in controlling pain, but many EM patients have found this combination has side effects that they are unable to tolerate.


title: Erythromelalgia

text: Only a small number of studies that have investigated the prevalence of EM, with four studies conducted to date.


title: Erythromelalgia

text: The mean of all the studies combined results in an EM estimation incidence of 4.7/100,000 with a mean of 1 : 3.7 of the male to female ratio, respectively.


title: Erythromelalgia

text: In 1997 there was a study conducted in Norway that estimated that the annual incidence of 2/100,000, with a 1 : 2.4 male to female ratio in this study


title: Erythromelalgia

text: population, respectively. In 2009 there was a population-based study of EM in the USA (Olmsted County, Minnesota), that reported that the annual incidence was 1.3/100,000, with a 1 : 5.6 male to female ratio in this study population, respectively.


title: Erythromelalgia

text: The incidence in this study of primary and secondary EM was 1.1 : 0.2 per 100 000 people per year, respectively.


title: Erythromelalgia

text: A study of a single centre in the south of Sweden in 2012, showed the overall annual population-based incidence was 0.36/100,000.


title: Erythromelalgia

text: In New Zealand (Dunedin) a study estimated that in 2013 the incidence of EM is 15/100,000, with a 1 : 3 male to female ratio in this study


title: Erythromelalgia

text: population, respectively. This last study has an estimation that is at least ten times higher than the prevalence previously reported. This study recruited individuals based on self-identification of symptoms (after self-identification, patients were invited for an assessment of an EM diagnosis), instead of participants that are identified through secondary and tertiary referrals as in the other studies.


title: Erythromelalgia

text: Epidemic EM appears quite common in female middle school students of southern China, most likely due to a sharp decline in temperature following by a rapid increase of temperature. It has been postulated that epidemic erythromelalgia might be related to a poxvirus (ERPV) infection. The disease was characterized by burning pain in the toes and soles of the feet, accompanied by foot redness, congestion, and edema; a few patients had fever, palpitations, headache, and joint pain. 60.6% of patients had a common cold before the onset of erythromelalgia and 91.2% had pharyngitis. For temperature-related theory, the acral (foot and hand) small superficial arteries intensely constrict and dilate during the sharp decline of temperature, whereas a sharp increase of temperature, the intense expansion of capillaries irritate the nerve endings around, and thus lead to syndromes including (first and second degree) burning pain, increased temperature, erythema and swelling.


title: Erythromelalgia

text: The first reported case was in 1878 by Silas Weir Mitchell who suggested the term erythromelalgia to describe a syndrome of red congestion and burning pain in the hands and feet.


title: Erythromelalgia

text: Some confusion was introduced when Smith and Allen suggested changing the name to erythermalgia in order to emphasise the symptoms of painful inflammation and warmth. In their paper they showed for the first time that when their patients used aspirin, this promptly relieved the burning pain for about three days. They also suggested a distinction between primary (idiopathic) erythromelalgia and secondary erythromelalgia (due to underlying neurologic, hematologic, or vascular problems).


title: Erythromelalgia

text: In 1994 Drenth, van Genderen and Michiels distinguished between erythromelalgia and erythermalgia on the basis of responsiveness to aspirin. They established three categories: erythromelalgia (platelet-mediated and aspirin-sensitive), primary erythermalgia, and secondary erythermalgia.


title: Erythromelalgia

text: Because of the confusion in terminology, Norton and Zager and Grady classified erythromelalgia in 1998 as either: primary/idiopathic erythromelalgia or secondary erythromelalgia. The primary/idiopathic form of erythromelalgia is not associated with any other disease process and can be either early onset (in children) or adult onset. In their paper they described secondary erythromelalgia as being associated with another disease, often related to a myeloproliferative disorder and has also seen cases of: hypertension, diabetes mellitus, rheumatoid arthritis, gout, systemic lupus erythematosus, multiple sclerosis, astrocytoma of the brain, vasculitis, and pernicious anemia.


title: Erythromelalgia

text: Because of the severity of the pain in erythromelalgia, and the lack of good pain medication then, there have been reports dating back to 1903 of amputation of the affected limb. In 1903 H. Batty Shaw reported that in three cases the pain was so severe, and that the affected extremities are so useless, that amputation was performed.


title: Erythromelalgia

text: Back in 1899 Thomas Barlow had already summarized with great detail the contrast between erythromelalgia and Raynaud's disease as following: "Dependence produces considerable increase of the dusky red or violaceous tint of the extremity affected; the arteries in this position of the limb may pulsate forcibly; pain is common, sometimes constant, and more especially when the limb is dependent or parts pressed upon; in wintry weather, or on the application of cold, the conditions are relieved; on the other hand, warmth and summer weather increases pain; there is no loss of sensation, but there may be increased sensitiveness; the local temperature of the affected parts may be raised or lowered; gangrene does not occur; the affection is asymmetrical; there is a certain amount of swelling, sometimes allowing pitting on pressure, sometimes not; incisions over such swelling, even down to the bone, have proved useless; excessive pain on pressure upon the nerves supplying the parts affected is not found; muscular wasting is found, but explainable by the disuse of the limb, and is not at all as severe as in cases of disease of the peripheral nerves; a reaction of degeneration in the nerves of the affected parts has not been found; the deep reflexes, with few exceptions, are not reduced."


title: DF-17

text: The Dongfeng-17 (), is a Chinese solid-fuelled road-mobile medium-range ballistic missile that mounts the DF-ZF Hypersonic Glide Vehicle.


title: DF-17

text: The DF-17 along with the DF-ZF, was officially unveiled at the National Day military parade on 1 October 2019, making this China's first operational hypersonic weapon systems and one of the world's first to be put in full initial operation.


title: DF-17

text: The DF-17 uses the rocket booster from the already operational DF-16B short-range ballistic missile. As such, the design of the missile itself did not require any major changes. The biggest change however, is the obvious usage of a hypersonic glide vehicle rather than a conventional re-entry warhead(s) found in normal ballistic missiles and MIRVs.


title: DF-17

text: The DF-ZF HGV operates in a different manner from normal ballistic missiles or even intercontinental ballistic missiles in the first place. Rather than firing and landing in a normal arc, the DF-17's HGV suppresses its trajectory and accelerates to reach Mach 5.


title: DF-17

text: Due to its suppressed, lower altitude trajectory, intercepting the glide vehicle with ABM shielding becomes far harder and more complex than that of a conventional re-entry vehicle. This is further complicated, as the gliding makes the DF-ZF far more maneuverable; extending both its range and avoiding potential ABM shielding. As such, the DF-17 could hit regional targets despite its SRBM nature. The DF-17 can also be used to mount a more conventional re-entry vehicle than the DF-ZF.


title: DF-17

text: Testing of DF-17 prototypes was underway by 2014. At least nine test flights occurred between January 2014 and November 2017.


title: DF-17

text: The HGV test flight of 1 November 2017 launched from the Jiuquan Satellite Launch Center in Inner Mongolia. The missile's payload flew approximately 1,400 kilometers with the HGV flying at a depressed altitude of around 60 kilometers following the completion of the DF-17’s ballistic and reentry phases. The test followed the first plenum of the Communist Party of China’s 19th Party Congress in October.


title: DF-17

text: In March 2020, the United States Department of Defense proposes to accelerate the development of conventionally armed hypersonic glide vehicles (HGV) to keep pace with the Chinese development. Michael Griffin, former Under Secretary of Defense for Research and Engineering, presented House Armed Services Committee that the United States needs to develop hypersonic weapons "to allow us to match what our adversaries are doing."


title: Ryan O'Connell

text: Ryan O'Connell is an American writer, actor, director, comedian, LGBTQ activist, and disability advocate. He is known for his 2015 memoir, "I'm Special: And Other Lies We Tell Ourselves", about his life as a gay man with cerebral palsy, which he adapted into television series "Special" for Netflix, which premiered in April 2019.


title: Ryan O'Connell

text: O'Connell grew up in Ventura County, California with what he described as his "liberal" family. He has a mild form of cerebral palsy (CP) since birth, which affects the right side of his body with a noticeable limp. Because of his CP, he had ten or eleven surgeries as a child, spending time in the hospital, and received much physical therapy.


title: Ryan O'Connell

text: Growing up, O'Connell requested TV scripts for Christmas, and watched shows with the closed captioning on to learn more about writing. He would watch shows and attempt to figure out the A-Plot versus the B-plot, and the structure of the script. He loved performing as well, acting in all the middle-school and high-school plays. Later on he suppressed this desire, seeing himself not represented in popular culture. He attended Foothill Technology High School.


title: Ryan O'Connell

text: He remained closeted until he was 17 and felt he needed to come out, to pursue another boy who was already out. His family was supportive when he did; his sister, uncle, and grandfather had already identified as LGBTQ.


title: Ryan O'Connell

text: When O'Connell was 20, he was hit by a car and required four hand surgeries. The accident resulted in compartment syndrome, and affected mainly his left hand. Nine months later, he moved to New York City to attend The New School. There, peers assumed his limp was from the car accident, and he chose not to correct them. He described feeling in limbo about his CP, not really fitting in with disabled or non-disabled people. Additionally, disabled representation in popular culture was nearly non-existent.


title: Ryan O'Connell

text: O'Connell worked as a blogger for three years, first serving as editor of "Thought Catalog" in 2011. He contributed to "Vice", "BuzzFeed", and other publications including "The New York Times" and "Medium". Some of his writing went viral and when he was 25, he was offered a book deal from Simon & Schuster. At the time, he kept his disability private. In 2015, he wrote a column for "Thought Catalog" called "Coming Out of the Disabled Closet" about hiding his disability with the car accident. He later expanded the article into his book, which he publicly revealed his disability. While writing the book, he moved to Los Angeles and at 27, started his television writing career with MTV's "Awkward".


title: Ryan O'Connell

text: Just as his second season with "Awkward" wrapped in 2015, his memoir "I'm Special: And Other Lies We Tell Ourselves" was published. In April 2015, Jim Parsons, who had read O'Connell's "Thought Catalog" article, optioned the book through his company That's Wonderful Productions which he runs with husband Todd Spiewak. O'Connell was assured with Parsons and Spiewak; he felt he could not trust a network with the gay content, fearing that they would let the project die after buying the option. In late 2015, O'Connell was named to the Out100 honoring LGBTQ icons.


title: Ryan O'Connell

text: In 2016, O'Connell received a go-ahead from Stage 13 to develop a script for "Special", based on his memoir, with eight 15-minute episodes for Netflix. The short-form format was taxing for the veteran script writer as there was no room for a C-plot alongside the A-Plot and B-plot, the writing also left no room, “every line needs to count for something and you can't do anything somewhere else.” "Special" was all written on weekends, as he was writing full-time. In December 2016, he completed the writing but still had obstacles getting it produced because of the disability angle. He started doing media work for "Special" while writing full-time on "BH90210," a Fox comedy-drama reboot of "Beverly Hills, 90210" which debuted in August 2019. He noted it was hard to launch a show with a gay lead character, let alone one who was also disabled; a first for television. He stated, "I think Hollywood is largely not interested in disabled people because they don't view us as 'sexy' or 'cool'." He lamented, "1 in 4 people identify as disabled and there are only two shows (me and "This Close") on the air from disabled people."


title: Ryan O'Connell

text: In "Special", the lead character Ryan misleads his coworkers that his limp was the result of a car accident instead of his cerebral palsy. The show is largely based on O'Connell's life. He uses the show to "explore his own internalized ableism and insecurities of being in the gay community". A 2016 Ruderman Family Foundation study found that "about 95% of characters with disabilities on television are played by able-bodied actors". Including actors with disabilities is still rare in entertainment industries; in 2018 Ali Stroker was “the first person in a wheelchair to win a Tony Award”; in July 2019, Marvel made history announcing a deaf superhero, a first; and AMC's "The Walking Dead" and HBO's "Years and Years" are among the few opening their casting.


title: Ryan O'Connell

text: Although he looked for an actor, ultimately he took the role himself due to budget constraints. The eight-episode season was shot over 19 days. Producers filmed with Austin, Texas doubling for Los Angeles, also due to budget constraints. He found in particular the sex scenes were emotionally taxing but also rewarding as disabled people having sex is rarely seen, and among LGBTQ people even rarer. O'Connell also "set out to depict onscreen sex in an authentic way, something rarely shown with LGBTQ people". He said, "I also want to live in a world where it's not groundbreaking to show an accurate sex scene between two men." "Special" also shows the lead character Ryan losing his virginity to a male sex worker in what O'Connell characterized as "a beautifully honest and sweet sex scene". "Digital Spy" noted "it's probably the first-ever TV show to tackle gay, disabled sex with authenticity, while destigmatising sex work at the same time." "USA Today" called the episode a landmark for disability representation and noted "O'Connell hope(s) to destigmatize sex work with the graphic scene, but also normalize gay sex for mainstream audiences who aren't used to seeing it in Hollywood movies or popular TV shows". O'Connell and the show were commended for his "standout performance and quippy prose".


title: Ryan O'Connell

text: O'Connell wrote for a season of "Daytime Divas" in 2017. He then worked as executive story editor on the 2017 reboot of "Will & Grace", which taught him to keep stories grounded in the characters even if the action gets "wacky". Additionally, he was co-host of the seminal podcast Babe? with the iconic Lara Marie Schoenhals.


title: Ryan O'Connell

text: In May 2019, O'Connell was honored with the HRC Visibility Award by the Human Rights Campaign at the 2019 HRC Atlanta Gala Dinner. In June 2019, O'Connell was the celebrity grand marshal for the LA Pride Parade. That month, "Queerty" named him one of the Pride 50 "trailblazing individuals who actively ensure society remains moving towards equality, acceptance and dignity for all queer people."


title: Ryan O'Connell

text: In July 2019, "Special" was nominated for four 71st Primetime Emmy Awards taking place in September: Outstanding Short Form Comedy or Drama Series; both Punam Patel and Jessica Hecht for Outstanding Actress in a Short Form Comedy or Drama Series; and O'Connell for Outstanding Actor in a Short Form Comedy or Drama Series. This is the most nominations for a short form piece this year.


title: Ryan O'Connell

text: In August 2019, it was announced that O'Connell and Anna Dokoza, an Australian director and producer who worked on "Special", as well as "Flight of the Conchords", and "Lady Dynamite", will be mentoring prospective producers in Australia. The effort, sponsored by SBS and Screen Australia, will launch Digital Originals, to make short-form projects for SBS On Demand.


title: Ryan O'Connell

text: In June 2022 O'Connell had his fiction debut with the book "Just by looking at him", also published by Simon & Schuster in New York.


title: Ryan O'Connell

text: O'Connell has been dating Jonathan Parks-Ramage since 2015. They met at Grimes birthday party in Los Angeles.


title: Michel Fourniret

text: Michel Paul Fourniret (4 April 1942 – 10 May 2021) was a French serial killer who confessed to killing 12 people in France and Belgium between 1987 and 2003. After he was arrested in June 2003 for the attempted kidnapping of a teenage girl in Ciney, Fourniret confessed to killing nine people — eight females and one male — in 2004, having been informed on by his then-wife, Monique Pierrette Olivier (born 31 October 1948). Fourniret was convicted of seven of these murders on 28 May 2008 and sentenced to life imprisonment without possibility of parole, while Olivier was given life with a minimum term of 28 years for complicity.


title: Michel Fourniret

text: In February 2018, Fourniret confessed to killing two more women. On 16 November 2018, Fourniret and Olivier were convicted of the murder of Farida Hammiche, the last of the eight women that Fourniret confessed to killing in 2004. Fourniret was given a second life sentence and Olivier was sentenced to a further 20 years of imprisonment. In March 2020, Fourniret confessed to killing Estelle Mouzin, who disappeared from Guermantes in 2003.


title: Michel Fourniret

text: Fourniret was born in Sedan, France, the son of a metal worker and a homemaker. Acquaintances remembered him as a quiet, intelligent child who enjoyed chess and classical music. He would later claim to have been sexually abused as a child by his mother. As an adult, he drifted through a series of menial jobs, including forestry worker and school supervisor.


title: Michel Fourniret

text: While in prison, Fourniret corresponded with Monique Olivier via a prison pen pal program. He wrote to her of his fantasies of raping and murdering virginal girls; she responded that she would "help" him fulfill those fantasies if he killed her husband, although he never committed this murder. After he was released from prison in 1987, they began a relationship. Soon afterward, he began raping and murdering young girls, with Olivier as his accomplice.


title: Michel Fourniret

text: On 11 December 1987, Fourniret and Olivier drove, in separate vehicles, to Auxerre. Seeing 17-year-old Isabelle whom the couple had seen a day or two earlier and were walking home from school, Olivier stopped to ask Laville to join her in the car and give her directions, which Laville agreed to do. Driving down the road, Olivier reached the spot where Fourniret was standing with his car, pretending it had broken down. After Olivier, as planned, pretended to offer him a lift, he got into her car. Fourniret choked Laville with a piece of rope, before Olivier sedated her with Rohypnol. The couple brought the girl to their home in Saint-Cyr-les-Colons, where Fourniret raped and strangled her. They threw Laville's body down a disused well in Bussy-en-Othe. Her remains were recovered from the well more than eighteen years later, on 11 July 2006.


title: Michel Fourniret

text: In March 1988, Fourniret was contacted by 30-year-old Farida Hammiche — the wife of Jean-Pierre Hellegouarch, an imprisoned bank robber with whom Fourniret had shared a cell prior to the latter's release in October 1987 — who asked Fourniret to help her unearth a haul from a cemetery in Fontenay-en-Parisis, which had been stolen by members of the "Gang des postiches". After Fourniret and Hammiche managed to retrieve the haul, which consisted of gold ingots and coins, Hammiche gave Fourniret a share worth 500,000 francs for helping her dig it up and hiding it in her apartment in Vitry-sur-Seine. On 12 April, aiming to steal Hammiche's share, Fourniret and Olivier lured Hammiche out of her home and drove her to Clairefontaine-en-Yvelines, where she was strangled and her body buried, before the couple broke into her home and stole the haul. They used the money they made from it to buy a château called the Château du Sautou in Donchery. Hammiche's body was never found.


title: Michel Fourniret

text: By August, Olivier was pregnant with Fourniret's baby. On 3 August, the couple drove to a supermarket in Châlons-sur-Marne (now Châlons-en-Champagne), and encountered 20-year-old Fabienne Leroy in the car park. With Olivier feigning illness, the couple asked Leroy to join them in their car and give them directions to a doctor's surgery. After Leroy got in, the couple drove to a forest near the military camp of Mourmelon-le-Grand. Fourniret ordered Olivier to look at Leroy's hymen to see if it was still intact, but Olivier refused. After raping Leroy, Fourniret shot her in the chest.


title: Michel Fourniret

text: In January 1989, Fourniret met 21-year-old Jeanne-Marie Desramault on the evening train to Charleville-Mézières. The two conversed before arriving in Charleville, where Desramault was staying at a convent. Desramault met Fourniret and Olivier, who had assumed false identities, at the train station again on 18 March, and the couple invited Desramault to come to their house in Floing – an offer she accepted – and Fourniret promised he would drive her home afterwards. After they got to Floing, Fourniret asked Desramault if she was a virgin, and she told him she was not and that she had a boyfriend. Enraged, he attacked her. She fought back as he attempted to rape her, and as she attempted to escape, the couple gagged her with adhesive bandages before Fourniret strangled her. Fourniret and Olivier drove to Donchery and buried Desramault's body in the garden of the Château du Sautou.


title: Michel Fourniret

text: Fourniret and Olivier married in July 1989. On the afternoon of 20 December, they drove across the Franco-Belgian border to Saint-Servais, Namur, with their one-year-old son. Fourniret saw 12-year-old Elisabeth Brichet walk to a friend's house, and waited outside for her until she left to walk the short distance home just before 7:00p.m. He asked her to give him directions to a doctor's surgery for his son. She agreed to do so, and the couple drove back to Floing with her. When Fourniret undressed the girl, he saw that she was menstruating, so Olivier cleaned Brichet's genitals. The next day, the couple took Brichet to the château, where Fourniret strangled her after a failed attempt to suffocate her with a plastic bag. Her body was buried in the garden of the château, near to that of Jeanne-Marie Desramault. There were a number of reported sightings of Brichet, in Belgium and abroad, in the years following her disappearance, and a number of people were suspected by police of abducting her, including another serial killer, Marc Dutroux. After Dutroux's arrest in 1996, Brichet's mother Marie-Noëlle Bouzet helped to organise the White March in honour of Belgium's missing and murdered children. The remains of Brichet and Desramault were exhumed from the gardens of the Château du Sautou on 3 July 2004, after Fourniret and Olivier confessed to the killings.


title: Michel Fourniret

text: The final known murder Fourniret committed with Olivier's help took place on 21 November 1990 near France's western coast. The couple drove to a shopping centre in Rezé after leaving court in Nantes, where they had been convicted of burglary. They saw Natacha Danais, a 13-year-old local girl, walking through the car park towards her home, having been sent to fetch her mother's forgotten purse. The couple lured Danais into the van, asking her for directions. After driving to a secluded area near the coast, Fourniret stabbed Danais twice in the chest with a screwdriver and strangled her before leaving her body on the beach. Later investigation suggested that the girl's body was raped after the murder. Eight days later, Jean Groix, a neighbour of Danais's family, was arrested after a white van belonging to him matched the description of the van that Danais' sister had seen her get into from across the shopping centre's car park at the time she disappeared. Groix was found to be lodging suspected members of the ETA in his home; police suspected that Danais had found out about this and that he killed her for that reason. Two months later, Groix committed suicide in his prison cell. He was reported to have been unable to bear the burden of having been accused of murder.


title: Michel Fourniret

text: The Fourniret family moved to Sart-Custinne, Gedinne, Belgium, in the early 1990s. Fourniret admitted that he committed two more murders in France between 2000 and 2001, his first in nine-and-a-half-years. He drove alone across the Franco-Belgian border to Charleville-Mézières on 16 May 2000 and lured 18-year-old Céline Saison, who was on her way home from school, into his van in the late afternoon. Driving with her back to Belgium, he raped her before strangling her with a rope and dumping her body in a forest in Sugny, Vresse-sur-Semois. Saison's skeletal remains were discovered there by mushroom pickers on 22 July 2000.


title: Michel Fourniret

text: On 5 May 2001, Fourniret drove back to Sedan and met Mananya Thumpong, a 13-year-old girl of Thai origin whom he had met and given a lift home a few weeks earlier, outside the local library. He invited her to come to his house and play with his son. Accepting this offer, Thumpong climbed into the van and was driven to Nollevaux, Paliseul, where Fourniret strangled her. Thumpong's remains were found on 1 March 2002, having been devoured almost entirely by wild animals.


title: Michel Fourniret

text: Fourniret was arrested at his home in Sart-Custinne, Belgium, on 26 June 2003 after a failed attempt to kidnap a 13-year-old girl. He and Olivier were interrogated extensively but to no avail. A year later, Olivier told the police that her husband had killed a number of people since 1987. Fourniret confessed to killing eight women — aged between 12 and 30 — and a man who has never been identified. The bodies of four of the identified victims had been discovered in France and Belgium between 1988 and 2002.


title: Michel Fourniret

text: Olivier was arrested, as well, and she and Fourniret were extradited to France, where they helped police find the bodies of three of the four missing victims over the next two years. The trial took place in Charleville-Mézières between 27 March and 28 May 2008. Fourniret was found guilty of the murders of all seven of the victims whose bodies had been found. He was sentenced to life in prison without the possibility of parole. Olivier was sentenced to life with no possibility of parole for 28 years. Fourniret and Olivier were also ordered to pay €1.5 million in moral compensation to family members of the victims. Neither appealed their sentences.


title: Michel Fourniret

text: Fourniret admitted to eight murders prior to his trial in 2008. He was convicted of seven of these and sentenced to life in prison.


title: Michel Fourniret

text: In February 2018, Fourniret confessed to killing two more women in Auxerre: Marie-Angèle Domèce, an 18-year-old disabled woman, in July 1988, and Joanna Parrish, a 20-year-old British student, in May 1990.


title: Michel Fourniret

text: In March 2020, Fourniret confessed to killing Estelle Mouzin, who disappeared from Guermantes in January 2003.


title: Michel Fourniret

text: Two French journalists have suggested that Fourniret killed former Minister for Labour Robert Boulin (who was involved in a real estate scandal at the time), based on a letter Fourniret wrote to Olivier.


title: Michel Fourniret

text: Christian Ranucci was one of the last people executed in France, having been convicted of the abduction and murder, committed on 3 June 1974, of Marie-Dolorès Rambla, aged eight. There were suspicions that Ranucci might not actually have been the killer, having confessed and later retracting his confession. It was suggested that Fourniret may have been involved, as Fourniret was thought to be in the area at the time and had virtually the same car as Ranucci. Careful analysis by an expert of courtroom photographs taken during Ranucci's March 1976 trial, however, suggests that the courtroom observer in the photographs could not have been Fourniret who, unlike this man, did not yet wear glasses and lacked a chin cleft. Furthermore, Fourniret denied having been in the Marseille area when the crime took place on 3 June 1974, claiming he was working in Paris.


title: Michel Fourniret

text: Rachida Dati, the then French Minister for Justice, who advocated legal reforms in France, wanted a more relaxed attitude to preventive custody and parole under supervision. She was heavily criticized by the judiciary.


title: Michel Fourniret

text: Fourniret died on 10 May 2021 at the age of 79 after being admitted into the hospital with respiratory problems.


title: Preboot Execution Environment

text: In computing, the Preboot eXecution Environment, PXE (most often pronounced as "pixie", often called PXE Boot/"pixie boot".) specification describes a standardized client–server environment that boots a software assembly, retrieved from a network, on PXE-enabled clients. On the client side it requires only a PXE-capable network interface controller (NIC), and uses a small set of industry-standard network protocols such as DHCP and TFTP.


title: Preboot Execution Environment

text: The concept behind the PXE originated in the early days of protocols like BOOTP/DHCP/TFTP, and it forms part of the Unified Extensible Firmware Interface (UEFI) standard. In modern data centers, PXE is the most frequent choice for operating system booting, installation and deployment.


title: Preboot Execution Environment

text: Since the beginning of computer networks, there has been a persistent need for client systems which can boot appropriate software images, with appropriate configuration parameters, both retrieved at boot time from one or more network servers. This goal requires a client to use a set of pre-boot services, based on industry standard network protocols. Additionally, the Network Bootstrap Program (NBP) which is initially downloaded and run must be built using a client firmware layer (at the device to be bootstrapped via PXE) providing a hardware independent standardized way to interact with the surrounding network booting environment. In this case the availability and subjection to standards are a key factor required to guarantee the network boot process system interoperability.


title: Preboot Execution Environment

text: One of the first attempts in this regard was bootstrap loading using TFTP standard RFC 906, published in 1984, which established the 1981 published Trivial File Transfer Protocol (TFTP) standard RFC 783 to be used as the standard file transfer protocol for bootstrap loading. It was followed shortly after by the Bootstrap Protocol standard RFC 951 (BOOTP), published in 1985, which allowed a disk-less client machine to discover its own IP address, the address of a TFTP server, and the name of an NBP to be loaded into memory and executed. BOOTP implementation difficulties, among other reasons, eventually led to the development of the Dynamic Host Configuration Protocol standard RFC 2131 (DHCP) published in 1997. The pioneering TFTP/BOOTP/DHCP approach fell short, as at the time, it did not define the required standardized client side of the provisioning environment.


title: Preboot Execution Environment

text: The Preboot Execution Environment (PXE) was introduced as part of the Wired for Management framework by Intel and is described in the specification published by Intel and SystemSoft. PXE version 2.0 was released in December 1998, and the update 2.1 was made public in September 1999. The PXE environment makes use of several standard client‑server protocols including DHCP and TFTP (now defined by the 1992 published RFC 1350). Within the PXE schema the client side of the provisioning equation is an integral part of the PXE standard and it is implemented either as a Network Interface Card (NIC) BIOS extension or current devices in UEFI code. This distinctive firmware layer makes available at the client the functions of a basic Universal Network Device Interface (UNDI), a minimalistic UDP/IP stack, a Preboot (DHCP) client module and a TFTP client module, together forming the PXE application programming interfaces (APIs) used by the NBP when needing to interact with the services offered by the server counterpart of the PXE environment. TFTP's low throughput, especially when used over high-latency links, has been initially mitigated by the TFTP Blocksize Option RFC 2348 published in May 1998, and later by the TFTP Windowsize Option RFC 7440 published in January 2015, allowing potentially larger payload deliveries and thus improving throughput.


title: Preboot Execution Environment

text: The PXE environment relies on a combination of industry-standard Internet protocols, namely UDP/IP, DHCP and TFTP. These protocols have been selected because they are easily implemented in the client's NIC firmware, resulting in standardized small-footprint PXE ROMs. Standardization, small size of PXE firmware images and their low use of resources are some of the primary design goals, allowing the client side of the PXE standard to be identically implemented on a wide variety of systems, ranging from powerful client computers to resource-limited single-board computers (SBC) and system-on-a-chip (SoC) computers.


title: Preboot Execution Environment

text: DHCP is used to provide the appropriate client network parameters and specifically the location (IP address) of the TFTP server hosting, ready for download, the initial bootstrap program (NBP) and complementary files. To initiate a PXE bootstrap session the DHCP component of the client's PXE firmware broadcasts a DHCPDISCOVER packet containing PXE-specific options to port 67/UDP (DHCP server port); it asks for the required network configuration and network booting parameters. The PXE-specific options identify the initiated DHCP transaction as a PXE transaction. Standard DHCP servers (non PXE enabled) will be able to answer with a regular DHCPOFFER carrying networking information (i.e. IP address) but not the PXE specific parameters. A PXE client will not be able to boot if it only receives an answer from a non PXE enabled DHCP server.


title: Preboot Execution Environment

text: After parsing a PXE enabled DHCP server DHCPOFFER, the client will be able to set its own network IP address, IP Mask, etc., and to point to the network located booting resources, based on the received TFTP Server IP address and the name of the NBP. The client next transfers the NBP into its own random-access memory (RAM) using TFTP, possibly verifies it (i.e. UEFI Secure Boot), and finally boots from it. NBPs are just the first link in the boot chain process and they generally request via TFTP a small set of complementary files in order to get running a minimalistic OS executive (i.e. WindowsPE, or a basic Linux kernel+initrd). The small OS executive loads its own network drivers and TCP/IP stack. At this point, the remaining instructions required to boot or install a full OS are provided not over TFTP, but using a robust transfer protocol (such as HTTP, CIFS, or NFS).


title: Preboot Execution Environment

text: The PXE Client/Server environment was designed so it can be seamlessly integrated with an already in place DHCP and TFTP server infrastructure.


title: Preboot Execution Environment

text: This design goal presented a challenge when dealing with the classic DHCP protocol. Corporate DHCP servers are usually subject to strict policies that are designed to prevent easily adding the additional parameters and rules required to support a PXE environment. For this reason the PXE standard developed the concept of DHCP redirection or "proxyDHCP". The idea behind a proxyDHCP is to split the PXE DHCP requirements in two independently run and administered server units:


title: Preboot Execution Environment

text: In a DHCP plus proxyDHCP server environment the PXE client initially broadcasts a single PXE DHCPDISCOVER packet and receives two complementary DHCPOFFERs; one from the regular non PXE enabled DHCP server and a second one from the proxyDHCP server. Both answers together provide the required information to allow the PXE client to continue with its booting process. This non-intrusive approach allows setting a PXE environment without touching the configuration of an already working DHCP server. The proxyDHCP service may also run on the same host as the standard DHCP service but even in this case they are both two independently run and administered applications. Since two services cannot use the same port 67/UDP on the same host, the proxyDHCP runs on port 4011/UDP. The proxyDHCP approach has proved to be extremely useful in a wide range of PXE scenarios going from corporate to home environments.


title: Preboot Execution Environment

text: PXE was conceived considering several system architectures. The version 2.1 of the specification defined architecture identifiers for six system types, including IA-64 and DEC Alpha. However, PXE v2.1 only completely covered IA-32. Despite this apparent lack of completeness Intel has recently decided to widely support PXE within the new UEFI specification extending the PXE functionality to all EFI/UEFI environments.


title: Preboot Execution Environment

text: Current Unified Extensible Firmware Interface Specification 2.4A, Section 21 Network Protocols — SNP, PXE, and BIS defines the protocols that provide access to network devices


title: Preboot Execution Environment

text: while executing in the UEFI boot services environment. These protocols include the Simple Network Protocol (SNP), the PXE Base Code Protocol (PXE), and the Boot Integrity Services Protocol (BIS).


title: Preboot Execution Environment

text: Today in a PXE environment the client architecture detection is rarely based on the identifiers originally included with the PXE v2.1 specification, instead each computer that will be booting from the network should have set DHCP option 93 to indicate the client's architecture. This enables a PXE server to know (at boot time) the exact architecture of the client from the first network boot packet. The client system architecture values are listed (among other PXE parameters) within the 2006 published RFC 4578 (Dynamic Host Configuration Protocol (DHCP) Options for the Intel Preboot eXecution Environment (PXE)).


title: Preboot Execution Environment

text: With the advent of IPv6 DHCP has evolved into DHCPv6; the need for options supporting PXE within the new DHCP protocol has been addressed by the 2010 published RFC 5970 (DHCPv6 Options for Network Boot).


title: Preboot Execution Environment

text: The original PXE client firmware extension was designed as an Option ROM for the IA-32 BIOS, so a personal computer (PC) was originally made PXE-capable by installing a network interface controller (NIC) that provided a PXE Option ROM. Today the client PXE code is directly included within the NIC's own firmware or as part of the UEFI firmware on the motherboard.


title: Preboot Execution Environment

text: Even when the original client PXE firmware has been written by Intel and always provided at no cost as a linkable IA32 object code format module included in their Product Development Kit (PDK), the open source world has produced over the years non-standard derivative projects like gPXE/iPXE offering their own ROMs. While Intel based ROMs have been implementing the client side of the PXE standard for more than 20 year some users were willing to trade extra features for stability and PXE standard conformance.


title: Preboot Execution Environment

text: PXE acceptance since v2.1 has been ubiquitous; today it is virtually impossible to find a network card without PXE firmware on it. The availability of inexpensive Gigabit Ethernet hardware (NICs, switches, routers, etc.) has made PXE the fastest method available for installing an operating system on a client when competing against the classic CD, DVD, and USB flash drive alternatives.


title: Preboot Execution Environment

text: In regard to NBP development there are several projects implementing Boot Managers able to offer boot menu extended features, scripting capabilities, etc.:


title: Preboot Execution Environment

text: All the above-mentioned projects, when they are able to boot/install more than one OS, work under a "Boot Manager - Boot Loader" paradigm. The initial NBP is a Boot Manager able to retrieve its own configuration and deploy a menu of booting options. The user selects a booting option and an OS dependent Boot Loader is downloaded and run in order to continue with the selected specific booting procedure.


title: Preboot Execution Environment

text: Apple has come up with a very similar network boot approach under the umbrella of the Boot Server Discovery Protocol (BSDP) specification. BSDP v0.1 was initially published by Apple in August 1999 and its last v1.0.8 was published in September 2010.


title: Preboot Execution Environment

text: The OS X Server includes a system tool called NetBoot. A NetBoot client uses BSDP to dynamically acquire resources that enable it to boot a suitable operating system. BSDP is crafted on top of DHCP using vendor-specific information to provide the additional NetBoot functionality not present in standard DHCP. The protocol is implemented in client firmware. At boot time, the client obtains an IP address via DHCP then discovers boot servers using BSDP. Each BSDP server responds with boot information consisting of:


title: Preboot Execution Environment

text: The client chooses an operating system from the list and sends a message to the server indicating its selection. The selected boot server responds supplying the boot file and


title: Preboot Execution Environment

text: Microsoft created a non-overlapping extension of the PXE environment with their Boot Information Negotiation Layer (BINL). BINL is implemented as a server service and it is a key component of their Remote Installation Services (RIS) and Windows Deployment Services (WDS) strategies. It includes certain preparation processes and a network protocol that could be somehow considered a Microsoft-crafted DHCP extension. BINL is a Microsoft proprietary technology that uses PXE standard client firmware. Currently there is not a publicly available BINL specification.


title: Vahana

text: Vahana (, or animal vehicle, literally "that which carries, that which pulls") denotes the being, typically an animal or mythical, a particular Hindu God is said to use as a vehicle. In this capacity, the vahana is often called the deity's "mount". Upon the partnership between the deity and his vahana is woven much iconography and Hindu theology. Deities are often depicted riding (or simply mounted upon) the vahana. Other times, the vahana is depicted at the deity's side or symbolically represented as a divine attribute. The vahana may be considered an accoutrement of the deity: though the vahana may act independently, they are still functionally emblematic or even syntagmatic of their "rider". The deity may be seen sitting or standing on the vahana. They may be sitting on a small platform, or riding on a saddle or bareback.


title: Vahana

text: In Hindu iconography, positive aspects of the vehicle are often emblematic of the deity that it carries. Nandi the bull, vehicle of Shiva, represents strength and virility. Dinka the mouse, vehicle of Ganesha, represents speed and sharpness. Parvani the peacock, vehicle of Kartikeya, represents splendor and majesty. The hamsa, vehicle of Saraswati, represents wisdom, grace, and beauty.


title: Vahana

text: However, the vehicle animal also symbolizes the evil forces over which the deity dominates. Mounted on Parvani, Kartikeya reins in the peacock's vanity. Seated on Dinka the rat (Mushika), Ganesha crushes useless thoughts, which multiply like rats in the dark. Shani, protector of property, has a vulture, raven, or crow within whom he represses thieving tendencies. Under Shani's influence, the vahana can make even malevolent events bring hope.


title: Vahana

text: Garuda, and his story of becoming the mount of Vishnu, is richly detailed in Hindu texts. Born to Vinata and bearing the power of Kashyapa's penance, the demigod is anguished to find that his mother is enslaved by the cruel Kadru. When he pleaded with Kadru to free his mother, the latter demanded the nectar of immortality as the price of her liberty. His legend of securing amrita, the nectar of immortality, is described in the episode known as "Amṛtakalaśāpaharaṇam"":"


title: Vahana

text: While the god Ganesha was still a child, a giant mouse began to terrorize all his friends. Ganesha trapped him with his lasso and made him his mount. Mushika was originally a gandharva, or celestial musician. After absent mindedly walking over the feet of a rishi (sage) named Vamadeva, Mushika was cursed and transformed into a mouse. However, after the rishi recovered his temper, he promised Mushika that one day, the gods themselves would bow down before him. The prophecy was fulfilled when the mouse became the vahana of Ganesha.


title: Vahana

text: Before becoming the vehicle of Shiva, Nandi was a deity called Nandikeshvara, lord of joy and master of music and dance. Then, without warning, his name and his functions were transferred to the aspect of Shiva known as the deity Nataraja. From half-man, half-bull, he became simply a bull. Since that time, he has watched over each of Shiva's temples, always looking towards him.


title: Vahana

text: Kartikeya, the war-god known as Murugan in Southern India, is mounted on a peacock named Paravani. This peacock was originally a demon called Surapadma, while the rooster was called the angel [Krichi]. After provoking Murugan in combat, the demon repented at the moment his lance descended upon him. He took the form of a tree and began to pray. The tree was cut in two. From one half, Murugan pulled a rooster, which he made his emblem, and from the other, a peacock, which he made his mount. In another version, Karthikeya was born to kill the demon, Tarakasura. He was raised by the Krittikas and led the divine armies when he was 6 days old. It is said that after defeating Tarakasura, the god forgave him and transformed him into his ride, the peacock.


title: Vahana

text: The animal correspondences of Hindu vehicles are not consistent with Greek and Roman mythology, or other belief systems which may tie a particular animal to a particular deity. For example, the goddess Lakshmi of the Hindus has elephants, or an owl, or (a rare instance of a non-animal vehicle) the lotus blossom as her vehicle. The goddess Athena of ancient Greece also had an owl as her emblematic familiar, but the meanings invested in the owls by the two different belief systems are not the same, nor are the two goddesses themselves similar, despite their mutual identification with owls.


title: Vahana

text: Lakshmi is, among other things, primarily the goddess of wealth, and her owl is a warning against distrust and isolationism, even selfishness. Athena, though also a goddess of prosperity, is primarily the goddess of wisdom, and her owl symbolizes secret knowledge and scholarship. Perhaps due to their shared geography, the Greco-Roman interpretation is paralleled in Roman Catholic iconography, in which St. Jerome, most famed for editing the New Testament, is often (though not always) depicted with an owl as a symbol of wisdom and scholarship. Depending on the tribe, Native American religious iconography attributes a wide range of attributes to the owl, both positive and negative, as do the Ainu and Russian cultures, but none parallel the Hindu attributes assigned to the owl as Lakshmi's divine vehicle.


title: Vahana

text: Some hold that similar analyses could be performed cross-culturally for any of the other Hindu divine vehicles, and in each case, any parallels with the values assigned to animal totems in other cultures are likely to be either coincidence, or inevitable (as in linking bulls to virility), rather than evidence of parallel development. In dialectic, this is countered by the retort that each totem or vahana, as an aspect of "ishta-devata" (or an "ishta-devata" or "asura" in its own right), has innumerable ineffable teachings, insights and spiritual wisdom; comparative analysis yields benefit, though knowledge and understanding is not served by collapsing their qualities into homogenous signification.


title: Vahana

text: These correspondences are not always consistent. Ganesha, for example, is sometimes shown with a peacock as his vehicle. Even more rarely, the elephant-headed Ganesh may be seen riding an elephant, or a lion, or a many-headed serpent (See Ganesha's Vahanas).


title: Vahana

text: The "vahana", the mount or vehicle of a deity, serves the function of doubling a deity's powers. The vahana also represents the devotee's mind which allows the deity to guide the devotee. Durga the warrioress could not have destroyed the demon Mahishasura without the aid of her vehicle, lion, which was given by her father Himalaya, for the stated purpose. Lakshmi, goddess of fortune, dispenses both material and spiritual riches from her mount, Uluka the owl. Ganesha, remover of obstacles, cannot go everywhere despite his elephant-like strength. However, his vehicle, Mushika the mouse, who can crawl into the smallest crevice or Akhuketana the rat, who can survive just about anywhere, can assist Ganesha to overcome the greatest obstacles.


title: Great Green Wall (Africa)

text: The Great Green Wall or Great Green Wall of the Sahara and the Sahel (; ) is a project led by the African Union, initially conceived as a way to combat desertification in the Sahel region and hold back expansion of the Sahara, by planting a wall of trees stretching across the entire Sahel. The modern green wall has since evolved into a program promoting water harvesting techniques, greenery protection and improving indigenous land use techniques, aimed at creating a mosaic of green and productive landscapes across North Africa.


title: Great Green Wall (Africa)

text: The project is a response to the combined effect of natural resources degradation and drought in rural areas. It seeks to help communities mitigate and adapt to climate change as well as improve food security. The population of the Sahel is expected to double by 2039, emphasizing the importance of maintaining food production and environmental protection in the area.


title: Great Green Wall (Africa)

text: In the 1950s the British explorer Richard St. Barbe Baker made an expedition in the Sahara. During St. Barbe's expedition he proposed a "Green front" to act as a tree buffer to contain the expanding desert. The idea re-emerged in 2002, at the special summit in N'Djamena, the capital of Chad on the occasion of World Day to Combat Desertification and Drought. It was approved by the Conference of Leaders and Heads of States members of the Community of Sahel-Saharan States during their seventh ordinary session held in Ouagadougou, the capital of Burkina Faso, on 1–2 June 2005. The African Union endorsed it in 2007 as the Great Green Wall for the Sahara and the Sahel Initiative (GGWSSI).


title: Great Green Wall (Africa)

text: Lessons learnt from the Algerian Green Dam and the Green Wall of China led to an integrated multi-sectoral approach. Originally a tree planting initiative, the project evolved into a development programming tool. In 2007, CHSG directed the project to tackle the social, economic and environmental impacts of land degradation and desertification. The countries Burkina Faso, Djibouti, Eritrea, Ethiopia, Mali, Mauritania, Niger, Nigeria, Senegal, Sudan and Chad thereafter created the Panafrican Agency of the Great Green Wall (PAGGW).


title: Great Green Wall (Africa)

text: A harmonised regional strategy was adopted in September 2012 by the African Ministerial Conference on Environment (AMCEN). According to AMCEN, the Great Green Wall is a flagship program that will contribute to the goal of the United Nations Conference on Sustainable Development, or RIO+20, of "a land degradation neutral world".


title: Great Green Wall (Africa)

text: In 2014, the European Union and the United Nations Food and Agriculture Organization, in collaboration with African and other regional partners, launched the Action Against Desertification program to build on the GGWSSI. Nigeria created an interim agency to support GGW development.


title: Great Green Wall (Africa)

text: Since 2014, the eco-friendly search engine Ecosia has been partnered with the local population in Burkina Faso. Ecosia spread its campaign to Ethiopia in 2017 and to Senegal the following year.


title: Great Green Wall (Africa)

text: According to Ecosia, it has planted over 15,117,046 trees and were restored in Burkina Faso; in Senegal it planted over 1,424,748 and restored and planted over 9,963,757 trees and restored in Ethiopia as of September 2021.


title: Great Green Wall (Africa)

text: Drylands Monitoring Week (2015) assessed the state of dryland measurement and initiated collaboration toward large-scale, comprehensive monitoring.


title: Great Green Wall (Africa)

text: Planning (including choices of vegetation and work with local populations) and plantings/land restoration followed (including in Ethiopia, Senegal, Nigeria and Sudan).


title: Great Green Wall (Africa)

text: In 2016, 21 countries had projects related to the GGW, including farmer-supported natural regeneration.


title: Great Green Wall (Africa)

text: Bare land restoration has been successfully demonstrated in Burkina Faso, although security is an issue in the face of terrorist activity.


title: Great Green Wall (Africa)

text: As of March 2019, 15 per cent of the wall was complete with significant gains made in Nigeria, Senegal and Ethiopia. In Senegal, over 11 million trees had been planted. Nigeria has restored 4.9 million ha (12 million acres; 49,000 km) of degraded land and Ethiopia has reclaimed 15 million ha (37 million acres; 150,000 km).


title: Great Green Wall (Africa)

text: In September 2020, it was reported that the Great Green Wall had only covered 4% of the planned area, with only 4 million hectares (9.8 million acres) planted. Ethiopia has had the most success with 5.5 billion seedlings planted, but Chad has only planted 1.1 million. Doubt was raised over the survival rate of the 12 million trees planted in Senegal.


title: Great Green Wall (Africa)

text: The Initiative brings together more than 20 countries, including Algeria, Burkina Faso, Benin, Chad, Cape Verde, Djibouti, Egypt, Ethiopia, Libya, Mali, Mauritania, Niger, Nigeria, Senegal, Somalia, Sudan, The Gambia and Tunisia.


title: Great Green Wall (Africa)

text: The project encompasses the Saharan strip, north and south borders, including Saharan oases and enclaves.


title: Great Green Wall (Africa)

text: The GGWSSI intends to strengthen existing mechanisms (such as Comprehensive African Agricultural Development Program, Environmental Program (CAADP) of New Partnership for Africa's Development (NEPAD), regional, sub-regional, and national action programmes to combat desertification) to improve their efficiency through synergy and coordination activities.


title: Great Green Wall (Africa)

text: The Regional Harmonised Strategy emphasizes partnerships between stakeholders, integration into existing programmes, sharing of lessons learnt (especially through South-South cooperation and technology transfer), local participation and ownership of actions and developing more integrated and global planning.


title: Great Green Wall (Africa)

text: The $8-billion project intends to restore 100 million hectares (250 million acres; 1 million km) of degraded land by 2030, which would create 350,000 rural jobs and absorb 250 million tonnes (250 million long tons; 280 million short tons) of from the atmosphere.


title: Gwadar Port

text: The Gwadar Port ( ) is situated on the Arabian Sea at Gwadar in Balochistan province of Pakistan and is under the administrative control of the Maritime Secretary of Pakistan and operational control of the China Overseas Port Holding Company. The port features prominently in the China–Pakistan Economic Corridor (CPEC) plan, and is considered to be a link between the Belt and Road Initiative and the Maritime Silk Road projects. It is about southwest of Turbat, and to the east of Chabahar Port (Sistan and Balochistan Province in Iran).


title: Gwadar Port

text: Gwadar's potential to be a deep water sea port was first noted in 1954, while the city was still under Omani sovereignty. Plans for construction of the port were not realised until 2007, when the port was inaugurated by Pervez Musharraf after four years of construction, at a cost of $248 million.


title: Gwadar Port

text: In 2015, it was announced that the city and port would be further developed under CPEC at a cost of $1.62 billion, with the aim of linking northern Pakistan and western China to the deep water seaport. The port will also be the site of a floating liquefied natural gas facility that will be built as part of the larger $2.5 billion Gwadar-Nawabshah segment of the Iran–Pakistan gas pipeline project. Construction began in June 2016 on the Gwadar Special Economic Zone, which is being built on 2,292-acre site adjacent to Gwadar's port. In late 2015, around 2000 acre land was leased to a Chinese company for 43 years for the development of Gwadar Special Economy Zone.


title: Gwadar Port

text: Gwadar Port became formally operational on 14 November 2016, when it was inaugurated by Pakistan's Prime Minister Muhammad Nawaz Sharif; the first convoy was seen off by the then Pakistan's Chief of Army Staff, General Raheel Sharif. On 14 January 2020, Pakistan operationalized Gwadar Port for Afghan transit trade. On 31 May 2021 Gwadar Port become fully Operational, along with the availability of online booking for the delivery of goods.


title: Gwadar Port

text: Gwadar Port is situated on the shores of the Arabian Sea in the city of Gwadar, located in the Pakistani province of Balochistan. The port is located 533 km from Pakistan's largest city, Karachi, and is approximately 120 km from the Iranian border. It is located away from Oman, and near key oil shipping lanes from the Persian Gulf. The greater surrounding region is home to around two-thirds of the world's proven oil reserves. It is also the nearest warm-water seaport to the landlocked, but hydrocarbon rich, Central Asian Republics, as well as Afghanistan.


title: Gwadar Port

text: The port is situated on a rocky outcropping in the Arabian sea that forms part of a natural hammerhead-shaped peninsula protruding out from the Pakistani coastline. The peninsula, known as the Gwadar Promontory, consists of rocky outcropping reaching an altitude of 560 feet with a width of 2.5 miles that are connected to the Pakistani shore by a narrow and sandy 12 kilometre long isthmus. The isthmus separates the shallow Padi Zirr bay to the west, from the deep water Demi Zirr harbour in the east.


title: Gwadar Port

text: Pakistan identified Gwadar as a port site as far back as 1954 when Gwadar was still under Omani rule. Pakistan's interest in Gwadar started when, in 1954, it engaged the United States Geological Survey (USGS) to conduct a survey of its coastline. The USGS deputed the surveyor, Worth Condrick, for the survey, who identified Gwadar as a suitable site for a seaport. After four years of negotiations, Pakistan purchased the Gwadar enclave from Oman for on 8 September 1958 (equivalent to in ) and Gwadar officially became part of Pakistan on 8 December 1958, after 200 years of Omani rule.


title: Gwadar Port

text: A small wharf at Gwadar was completed in 1992, and formal proposals for a deep sea port at Gwadar were unveiled a year later in 1993. The federal government approved the construction of the port in December 1995 but the project could not get started because of shortage of funds. In 1997, a government-appointed task force identified Gwadar as one of the focus area of development, but the project did not launch due to economic sanctions imposed against Pakistan following its nuclear tests in May 1998. Construction on Phase 1 of the project began in 2002 after the agreement for its construction was signed during the state visit of Chinese Premier Zhu Rongji in 2001. After completion of Phase 1 in 2007, the first commercial cargo vessel to dock at the port was the "Pos Glory," with 70,000 Metric Tonnes of Wheat on 15 March 2008.


title: Gwadar Port

text: The port is part of the 21st Century Maritime Silk Road that runs from the Chinese coast through the Strait of Malacca, to Mombasa, from there via the Suez Canal to the Mediterranean, there to the Upper Adriatic region with its rail connections to Central Europe and the North Sea.


title: Gwadar Port

text: Gwadar Port is being developed in two phases: Phase I covered building of three multipurpose berths and related port infrastructure and port handling equipment, and was completed in December 2006, but inaugurated on 20 March 2007.


title: Gwadar Port

text: The first phase of construction at Gwadar Port began in 2002, and was completed in 2006, before inauguration in 2007.


title: Gwadar Port

text: The second phase of construction is currently underway as part of planned improvements under CPEC and other ancillary projects. The total project is expected to cost $1.02 billion. In Sep 2018, the Pakistan Senate expressed concern at slow rate of progress of most projects of Phase II at Gwadar as construction had not started for most projects.


title: Gwadar Port

text: Under the China-Pakistan Economic Corridor plan, the state-owned China Overseas Port Holding Company (COPHC) will expand Gwadar Port with construction of nine new multipurpose berths on 3.2 kilometres of seafront to the east of the existing multipurpose berths. COPHC will also build cargo terminals in the 12 kilometres of land to the north and northwest of the site along the shoreline of the Demi Zirr bay.


title: Gwadar Port

text: In total, COPHC has awarded $1.02 billion worth of contracts for expansion of the port. In addition to construction of nine berths and cargo terminals, plans for expanded port infrastructure also include several projects that will be financed by loans extended by Chinese state owned banks. The Gwadar Port dredging project will deepen approach channels to a depth of 14 meters from the current 11.5-meter depth, at a cost of $27 million. Dredging will enable docking of larger ships with a deadweight tonnage of up to 70,000 at Gwadar Port, while current capacity permits a maximum 20,000 DWT. Future plans call for dredging of the harbour to a depth of 20 meters to allow for docking of larger vessels. Also included as part of the CPEC infrastructure development package for port infrastructure is a $130 million breakwater around the port.


title: Gwadar Port

text: Ancillary infrastructure projects for the port will also be built as part of CPEC. A $114 million desalination plant will be developed to provide potable water to the city, while the Government of Pakistan will also contribute $35 million towards infrastructure projects in the Gwadar Special Economic Zone. A 19 kilometre-long dual carriageway known as the Gwadar East Bay Expressway will also be built at a cost of $140 million to connect Gwadar Port to the existing Makran Coastal Highway and the planned $230 million Gwadar International Airport.


title: Gwadar Port

text: A floating liquefied natural gas facility that will have a capacity of 500 million cubic feet of liquified natural gas per day will also be built at the port as part of the $2.5 billion Gwadar-Nawabshah segment of the Iran–Pakistan gas pipeline, which is being built as a joint venture between Pakistan's Inter State Gas System, and the China National Petroleum Corporation. The Pakistani government also intends to establish a training institute named Pak-China Technical and Vocational Institute at Gwadar which is to be completed at the cost of 943 million rupees to impart skills to local residents to train them to operate machinery at the port.


title: Gwadar Port

text: It was expected that by 2017, the port will handle over one million tons of cargo, most of which will consist of construction materials for other CPEC projects. However, the project has faced multiple challenges. The Pakistan government has curbed expansion of mega project due to mounting debt on country's exchequer. The Covid19 pandemic has further impacted the work on the project. COPHC plans to eventually expand the port's capacity to 400 million tons of cargo per year. Long terms plans for Gwadar Port call for a total of 100 berths to be built by 2045.


title: Gwadar Port

text: In Sep 2018 the Ministry of Maritime of Pakistan submitted a report in Senate that during the last five years, 99 ships loaded with cargo from seven different countries anchored at Gwadar Port. The weight of shipments was 1.439 million tons.


title: Gwadar Port

text: The government of China in August 2015 announced that the previously announced concessionary loans for several projects in Gwadar totalling $757 million would be converted 0% interest loans for which Pakistan will only be required to repay the principal value. The projects which are now to financed by the 0% interest loans include: the construction of the $140 million East Bay Expressway project, installation of breakwaters in Gwadar which will cost $130 million, a $360 million coal power plant in Gwadar, a $27 million project to dredge berths in Gwadar harbour, and a $100 million 300-bed hospital in Gwadar.


title: Gwadar Port

text: In September 2015, the government of China also announced that the $230 million Gwadar International Airport project would no longer be financed by loans, but would instead be constructed by grants which the government of Pakistan will not be required to repay.


title: Gwadar Port

text: The expanded port will be located near a 2,282-acre free trade area in Gwadar which is being modelled on the lines of the Special Economic Zones of China. The 2000 acre of land was leased to Chinese Company in November 2015 for the construction of Gwadar Economic Zone., while construction of the project began on 20 June 2016. The special economic zone is expected to employ approximately 40,000 people, with possibility for future expansion.


title: Gwadar Port

text: The special economic zone will include manufacturing zones, logistics hubs, warehouses, and display centres. Business established in the special economic zone will be exempt from Pakistani income, sales, and federal excise taxes for 23 years. Contractors and subcontractors associated with China Overseas Port Holding Company will be exempt from such taxes for 20 years, while a 40-year tax holiday will be granted for imports of equipment, materials, plants, machinery, appliances and accessories that are to be for construction of Gwadar Port and special economic zone.


title: Gwadar Port

text: The special economic zone will be completed in three phases. By 2025, it is envisaged that manufacturing and processing industries will be developed, while further expansion of the zone is intended to be complete by 2030. On 10 April 2016, talking to "The Washington Post", Zhang Baozhong, chairman of China Overseas Port Holding Company said that his company could spend a total of $4.5 billion on roads, power, hotels and other infrastructure for the industrial zone, which he said would be open to non-Chinese companies. The company also plans to build an international airport and power plant for Gwadar.


title: Gwadar Port

text: Gwadar Port is owned by the government-owned Gwadar Port Authority and operated by China Overseas Port Holding Company (COPHC), a state-run Chinese firm. Prior to COPHC, the port was operated by the Port of Singapore Authority.


title: Gwadar Port

text: Following the completion of Phase I, the Government of Pakistan in February 2007 signed a 40-year agreement with PSA International for development and operation of the port, and an adjacent 584-acre special economic zone. PSA International was the highest bidder for the Gwadar Port, after its competitor DP World withdrew from the bidding process. PSA was granted a wide range of tax concessions, including exemption from corporate tax for 20 years, land for a special economic zone, duty-free imports of materials and equipment for construction and operations of the port, and duty-free shipping and bunker oil for 40 years. In addition to these incentives, the provincial government of Balochistan was also asked to exempt PSA International from the levy of provincial and district taxes. According to the agreement with PSA, the Government of Pakistan was to get a fixed 9% share of the revenue from cargo and maritime services, in addition to 15% of revenues earned from the adjacent special economic zone.


title: Gwadar Port

text: In September 2011, "The Wall Street Journal" reported that Gwadar was being underused as commercial port, and that Pakistan had asked the Chinese government to assume operations of the port.


title: Gwadar Port

text: PSA also reportedly sought to withdraw from its contract with the Pakistani Government, and expressed willingness to sell its share in the project to a Chinese firm after the Pakistani Navy failed to transfer land required for development of the planned 584-acre free trade zone. PSA also did not invest the agreed $550 million into the port, on account of the poor security situation in Balochistan in the period between 2007 and 2013.


title: Gwadar Port

text: The government of Pakistan also failed to invest in requisite infrastructure works. The Supreme Court of Pakistan further issued a stay order against the allotment of land to PSA on account of a public petition.


title: Gwadar Port

text: On 18 February 2013, Pakistan awarded a contract for construction and operation of Gwadar Port to a Chinese state-owned enterprise. As per details of the contract, the port would remain as property of Pakistan, but would be operated by the state-run Chinese firm – China Overseas Port Holding Company (COPHC). The contract signing ceremony was held on 18 February 2013 in Islamabad, and was attended by Pakistani President Asif Ali Zardari, Chinese Ambassador Liu Jian, as well as various federal ministers and members of parliament, as well as senior government officials. The ceremony was also marked the transfer of the concession agreement from the PSA to the COPHC.


title: Gwadar Port

text: As per this agreement, 91% of the revenue generated by Gwadar Port will go to COPHC and 9% to Gwadar Port Authority. In March 2019, the Pakistani Senate was informed that during last three years, total gross revenue of Rs 358.151 million had been generated from Gwadar Port, out of which the share going to Gwadar Port Authority was Rs 32.324 million.


title: Gwadar Port

text: The Straits of Malacca provide China with its shortest maritime access to Europe, Africa, and the Middle East. Approximately 80% of its Middle Eastern and African energy imports also pass through the Straits of Malacca. As the world's biggest oil importer, energy security is a key concern for China while current sea routes used to import Middle Eastern and African oil are frequently patrolled by the United States Navy. The sea-route via the Straits of Malacca is roughly , while the distance from Gwadar Port to Xinjiang province is approximately , and another from Xinjiang to China's eastern coast. However, the cost of moving oil overland is far greater. An oil pipeline from Gwadar to China's population centers (not yet built), will cost up to $8/barrel, while the cost of shipping oil from the Persian Gulf to China is $2–3/barrel.