Guide Badface Investigates - Volume 1

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Coinsquare faking volume : BitcoinCA

The Blockchain Transparency Institute confirms this. They are exaggerating volume by a factor of ! I practically did that myself lol. Use critical thinking in the future before you share these ideas with others, you'll look like less of a moron. Never done withdrawals with them.


I send to an external exchange to withdraw. Well they advertise themselves as "Canada's biggest exchange" which is already a scam so.. Hello ameliamckelvey ,. Charlie here from Coinsquare Customer Success team. We do not fake our volume and I do not believe a member of our team would ever say that to a customer.


If you are having an issue or would like to provide feedback I would recommend contacting support again. I'm having trouble figuring out how such huge volumes of trades go through at prices between the highest bid and the lowest ask in the ETH and LTC books. I'm not saying this is 'faking the volume', but I agree with the poster above that this volume does not belong in the order history, as those sales were never available to people using the exchange.

Whether or not the API should report it in trade volume is open for discussion, and it's certainly hard to deny CS from claiming that to be part of their volume when quoting how big of an exchange they are in terms of volume. It's particularly frustrating for me, as I often sit at the lowest ask when I have alts to sell, but see way more than my asking volume go through at prices below mine that never appeared below me in the order book.

It appears to me that the only volume I would get as the lowest ask is from someone making a quick trade or making a market buy, and not from the OTC trades above. The only volume that seems suspicious I've noticed on your litecoin pair. Do you mind investigating these trades and addressing this? Remarkably, many lesion-resident molecules activate pathways leading to both suppression of inflammation and promotion of repair mechanisms.

These guardian molecules and their corresponding physiologic pathways could potentially be exploited to silence inflammation and repair the injured and degenerating brain and spinal cord in both relapsing-remitting and progressive forms of MS and may be beneficial in other neurologic and psychiatric conditions. It is difficult to say a favorable word about a terrible disease, but one of the positive features of multiple sclerosis MS is the remarkable capacity for patients to spontaneously recover from neurologic deficits that are attributed to inflammatory attacks on the CNS.

Most of the neurologic deficits in these recurrent acute attacks, known as relapses after the initial episode, resolve nearly completely over a few days to a few weeks 1. For example, an attack on the optic nerve can leave an individual unable to read for a few days or weeks, but in many cases, there is full recovery of visual acuity after the initial neurologic insult. An attack within the pyramidal system in the brain or spinal cord may cause paralysis of a limb, but often there is recovery from this deficit over days and weeks in the early stages of MS.

Despite these remissions, the course of disease advances over a decade or more in about a quarter of individuals. In these unfortunate individuals, relapsing-remitting disease transitions to secondary progressive MS, which is characterized by a large burden of disability and a lack of distinct relapses 1. The substantial and remarkable recovery remission from an inflammatory insult relapse is a well-known phenomenon; however, more attention has been given to analyzing the inflammation that produces clinical deficits than to the processes that account for remission.

The brain in MS frequently responds to immune damage with an array of molecules that serve to protect it from further damage and to foster recovery. This beneficial response to injury may be coordinated. Both cells extrinsic and intrinsic to the CNS are involved in the production of these guardian molecules. Some guardian molecules enter the somewhat privileged site of the brain via infiltrating immune cells 1 — 6 , still others are present at the blood-brain barrier that forms an interface between the immune system and the brain 7 — 11 , while others are produced within the CNS itself 12 — This Review will describe these guardian molecules including protective cytokines like type 1 interferon, IL, and IL; the neurotrophins; neurotransmitters like GABA; antioxidants; small lipids present in the normal myelin sheath; nuclear hormone receptors; amyloid-forming molecules; and serpins and other inhibitory proteins.

All these molecules may serve as platforms for novel restorative therapies, provided they can be delivered to the brain structures under attack. The immune attack in MS is driven primarily by the migration of lymphoid cells from outside the brain. T cells, B cells, and macrophages must move across the inflamed endothelium into brain via venules at the blood-brain barrier.

The nature of this external attack on the CNS is best appreciated from studies leading to the development of the FDA-approved drug natalizumab Figure 1 , which is widely regarded as the most potent therapeutic to date for relapsing-remitting MS RRMS. This therapy is associated with a marked reduction in inflammatory lesions, as measured by MRI. This interaction gives lymphocytes access to the CNS. The presence of immune cells in the brain is a prominent feature of MS. Reproduced with permission from ref. Journal of Cell Biology. However, immune cells migrating into the brain also produce cytokines like IL and IL, two cytokines with suppressive properties that attenuate inflammation 5 , Protective cytokines like IL are also produced by resident glia or neurons in response to injury.

Activated microglia produce IL, which in turn suppresses neuroinflammation. The infiltrating lymphocytes then carry these suppressive cytokines to the locus of disease within the CNS. This is an example of how secretion of guardian molecules from cells that are not normally in the CNS may be an unexpected beneficial consequence of the migration of lymphocytes, particularly since this migration includes immune cells that induce disease in the first place. Neurotrophins, including brain-derived neurotrophic factor BDNF and nerve growth factor NGF , have long been regarded as molecules that promote neural outgrowth, but they are also imbued with antiinflammatory properties.

Neurotrophins are produced in the brain at the site of disease as well as by the lymphoid cells that migrate into the brain in MS 20 , 21 , 51 , where they contribute to resolution of neuroinflammation. Certain polymorphisms in BDNF, including Val66Met, are protective in individuals with MS and are associated with a slower decrease in brain volume as disease progresses 53 , NGF may also have a beneficial role in MS.

NGF can be detected in active MS lesions with mass spectroscopy 6 and by immunohistochemical techniques The NGF receptor was present in active lesions on astrocytes and microglia, as well as on infiltrating lymphocytes A pattern appears again in these dual properties of neurotrophin molecules, which exert both antiinflammatory and growth-promoting effects on neurons. Molecules imbued with these properties act to both inhibit inflammation and promote regrowth in the nervous system. These observations also emphasize that the injured brain fights back to restore itself after injury.

Pharmacologic agents that activate GABA are able to modulate T cell function 12 , 58 and reduce ongoing paralytic disease and brain inflammation in various animal models of EAE The effect of GABA and drugs that increase GABA activity also show efficacy in models of other inflammatory diseases including inflammatory bowel disease 59 , and in type 1 diabetes Thus, GABA serves not only as an inhibitory neurotransmitter, but also exerts a parallel inhibitory effect on inflammation in the brain as well as on other organ systems.

Clinical trials with pharmacological agents that affect GABA are planned. Redox is implicated in the inflammatory pathology in general, and glutathione metabolites involved in glutathione metabolism, including glutathione synthase and various glutathione transferases, are expressed in active and chronic MS lesions 6.

Molecules associated with maintaining a physiological redox state, including cystathione and glutathione, which are present in the brain, serve as regulators of the inflammatory response. A coordinated antioxidant response in MS is in part controlled by the transcription factor nuclear factor erythroid-derived 2 —like 2 NRF2. Activation of NRF2 leads to increased production of a spectrum of antioxidants, including glutathione and cystathionine NRF2 is activated upon its translocation to the nucleus, which is dependent on the modification of free cysteine residues, a process known as sulfhydration, in the NRF2-binding adaptor protein kelch-like ECH-associated protein KEAP1.

The drug dimethylfumarate, which targets the NRF2 pathway, is approved for treatment of RRMS 62 , 63 and is under investigation in clinical trials in progressive forms of MS. Dimethylfumarate has pleiotropic mechanisms of action, but activation of NRF2 accounts for some of its antiinflammatory activity 16 , 17 , When KEAP1 undergoes sulfhydration of cysteine via binding of fumarate, it becomes unable to interact with NRF2, which accumulates in the nucleus and induces the expression of NRF2-dependent antioxidant and cytoprotective genes.

The antioxidant activities may support its use in neurodegenerative processes associated with progressive forms of MS. It is remarkable that a small molecule like dimethylfumarate can lead to activation of a single transcription factor with such potent activity on the inflammatory component of MS.

C. L. I. F. S1 警徽天职 1 - Ep 2

But activation of multiple beneficial pathways with a single small molecule is seen repeatedly in biology and medicine. Small molecules, including glutathione, cysteine, the neuroprotectant cystathionine, and the gaseous neurotransmitter H 2 S, play a key role in attenuating neurological injury. In experimental models of MS, elevation of cysteine via administration of cystamine or N -acetylcysteine ameliorates paralysis in the EAE model 18 , Recent reports show that there may be clinical benefit of cysteamine in treating HD 70 , Cysteamine also induces production of BDNF, which has both antiinflammatory and neurotrophic properties, as discussed above 68 , These small molecules also catalyze sulfhydration 64 , 65 , As described above, the interplay of sulfhydrates on KEAP1 has remarkable similarities to the mechanism of action of dimethylfumarate Figure 2 in allowing the nuclear translocation of NRF2.

Proteomic platforms allow us to analyze the various molecules that bind small-molecule mediators like dimethylfumarate and cysteamine Such analysis will elucidate the parallel biochemical pathways that might be mediated in attenuating not only inflammation in the CNS, but the degenerative processes 73 , Inflammation and oxidative stress are thought to promote tissue damage and MS, and recent data point to a protective role for antioxidant pathways, including the transcription factor NRF2, in MS.

Dimethylfumarate has pleiotropic mechanisms of action, but activation of NRF2 accounts for some of its antiinflammatory activity. B When KEAP1 undergoes sulfhydration of cysteine via binding of fumarate, it becomes unable to interact with NRF2, which accumulates in the nucleus and induces the expression of NRF2-dependent antioxidant and cytoprotective genes. Activation of NRF2 leads to increased production of a spectrum of antioxidants, including glutathione and cystathionine.

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Gaseous neurotransmitters, also known as gasotransmitters 13 , 14 , like H 2 S involved in sulfhydration and NO involved in nitrosylation , are not the only gaseous protectants from neuroinflammation. HMOX1 dampens inflammatory reactions via the catabolism of heme into CO, iron, and biliverdin in the brain, liver, spleen, and endothelium 75 , Enhancing levels of gaseous neurotransmitters is under serious consideration as a neuroprotective therapy for MS on the basis of its success in animal models, in which delivery of CO via inhalation of CO, compared with room air, arrested EAE progression and paralysis We used lipid antigen microarrays and lipid mass spectrometry to identify the lipid targets that react with antimyelin antibodies in MS brain.

We reported that autoantibodies in MS target a phosphate group in phosphatidylserine and oxidized phosphatidylcholine derivatives. Remarkably, when administered systemically, these same lipids that are targeted via antibodies actually ameliorated experimental autoimmune encephalomyelitis.

The mechanism of action was via suppression of activation of autoreactive T cells as well as induction of apoptosis of autoreactive T cells Thus, substituents of naturally occurring phospholipids represent a natural antiinflammatory class of compounds that have potential as therapeutics for MS Other naturally occurring lipids are proinflammatory. Lactosylceramide activates microglia and astrocytes and contributes to neurodegenerative processes in experimental neuroinflammation Females are far more susceptible to MS than are males, and this ratio has been increasing over the past 50 years 1.

In investigating some of the factors controlling this dimorphism in susceptibility, we have encountered a potent brake on the immune system that may play an import role in neuroinflammation and neurodegeneration. The PPARs are a family of nuclear hormone—activated receptors that act as transcription factors. These receptors are activated by sex hormones, lipids, and fatty acids 22 — Females are far more susceptible to disease In , Dunn and we translated these studies to humans Female humans exhibit much stronger Th1 responses than do males, while males exhibit stronger Th17 responses than do females.

One of the major implications of these studies is that androgen-driven transcription factors serve as a major braking system on both Th1 and Th17 T cell responses 22 , This braking system is operative in the peripheral immune system, but controls the expression of inflammation in the brain in EAE. One of the most surprising developments in deciphering which molecules may serve as guardians in MS arose from an analysis of molecules found in MS lesions 84 , In , we published a report on the transcriptome of acute and chronic lesions in MS 41 , Two years later, working with the same blocks of tissue, we performed proteomic analysis of laser-captured, microdissected lesions 6.

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We noted that several amyloid-forming molecules, including CRYAB, amyloid precursor protein APP , major prion protein, and tau, were all found in lesions that were laser captured, microdissected, and subjected to mass spectral analysis 6. Most of us continue to think of amyloid-forming molecules as harmful. In MS, there is a significant imprint of inflammation with perivascular infiltrates, with evidence of both innate immunity and adaptive immunity at the T and B cell levels To refer to neuroinflammation in AD is perhaps to give new meaning to the word inflammation.

We make these transformations in language all the time, and this may be an example in the realm of biomedical science. Numerous phase 3 trials using these strategies have failed 90 , Could amyloid molecules have a different role in MS 30 , 31? Research on MS and its animal models point in this direction. The effects were robust in several versions of EAE, including in models of progressive disease and relapsing-remitting disease. CRYAB was also efficacious in models of stroke, myocardial infarction, optic nerve ischemia, and rheumatoid arthritis 92 — Investigations in optic nerve ischemia showed that administration of CRYAB after disease onset induced complete rescue of the optic nerve oligodendrocytes from the ischemic insult These experimental results suggest that amyloid-forming proteins, which are found in actual lesions in MS, may serve to contain ongoing inflammation and initiate repair.

Among the various amyloid-forming molecules, the case is strongest for CRYAB in protecting and reversing neuroinflammation and in protecting myelin-forming oligodendrocytes. While we have shown in gain-of-function experiments that administration of amyloid-forming proteins such as CRYAB improves function in EAE, stroke, myocardial infarction, and optic nerve ischemia 92 — 96 , loss-of-function experiments with genetic deletion of amyloid-forming proteins provide further support for the notion that amyloid proteins and peptides are beneficial.

Mice lacking APP also have more severe functional disturbances following blunt brain trauma Taken together, the gain-of-function and loss-of-function experiments indicate that amyloid molecules forming self-assembling, zippered nanostructures are potent mediators of protection and repair.