Green tea component may hinder virulent virus …

EGCG Inhibits Ebola Replication
Obstructs chaperone essential for virus infection

By Will Block

Aragorn: Are you frightened?
Frodo: Yes.
Aragorn: Not nearly frightened enough.

The Lord of the Rings: The Fellowship of the Ring (2001 movie)

T

Figure 1 Without the activity of the HspA5 chaperone, proper folding fails and the Ebola protein is marked for degradation.
LEM1411proteindiagram274.gif
(click on thumbnail for full sized image)

he frightening outbreak of the highly virulent Ebola viruses in Africa, the U.S., Spain, and elsewhere—producing scenes out of Dante’s Inferno—necessitates that new strategies to defeat Ebola be given extreme priority. Pursuing this urgent goal, a striking report from the United States Army Medical Research Institute of Infectious Diseases at Fort Detrick has just been published in the highly regarded refereed journal Antiviral Research.1 This new study points to the heat shock protein A5 (HspA5), an Ebola-associated host factor that resides in the endoplasmic reticulum (ER) where proteins are synthesized and folded. As a highly conserved ER-resident protein, HspA5 acts as a host chaperone for the folding and assembly of budding proteins—including the dreaded Ebola. However, when HspA5 is prevented from acting, proteins such as Ebola are misfolded and marked for degradation (see Fig. 1).


HspA5 acts as a host chaperone for
the folding and assembly of budding
proteins, including the dreaded Ebola.


The Fort Detrick facility views itself as the birthplace of medical biodefense. They also boast that they have the largest containment laboratory in the U.S., from which there has never been a release of any dangerous organism outside its environment. Adherence to high-level biohazard standards is especially important for Ebola containment.*

Inhibiting Viral Refolding

In their new paper, the Fort Detrick researchers show that epigallocatechin gallate (EGCG), a principal component of green tea, is essential for Ebola virus infection protection because it inhibits the chaperone HspA5. These findings demonstrate that HspA5 is vital for Ebola replication—but when blocked, the growth of the virus is halted under laboratory conditions.

Ebola Causes Multiple Organ Failures and Bleeding

Ebola is a filovirus, a virus that causes hemorrhagic fever leading to multiple organ malfunctions and ultimate failures. Victims bleed from every orifice and skin hemorrhages. See the photographs if you dare! Structurally, Ebola looks like an unevenly inflated and broken strand of spaghetti. The protein envelope that Ebola generates surrounds a strand of RNA, which is similar but simpler than a stand of DNA. An Ebola strand of RNA has been described as pure information with instructions for replication.

“Successful” Ebola virus infection requires effective recruitment of host factors for the various stages of the viral life cycle. There are currently no approved therapeutic strategies for treating Ebola infection (although blood transfusions from Ebola survivors who have developed antibodies may be one such strategy). Consequently, the absolute dependence on these host factors, owing in large part to the limited number of viral gene products offers a promising area for therapeutic intervention. Toward this end, the researchers have identified the ER chaperone HspA5 as an Ebola-associated host promoter.

Scientists have established that HspA5 is a highly conserved§ ER-resident protein involved in the folding and assembly of budding proteins. As a chaperone, it also serves as master regulator of ER stress. Proteins synthesized in the ER are properly folded with the assistance of ER chaperones, such as HspA5. Mal-folded proteins are disposed of by ER-associated protein degradation (ERAD; see Fig. 1).

The ER Stress Response

When the amount of unfolded protein exceeds the folding capacity of the ER, human cells activate a defense mechanism called the ER stress response, which induces expression of ER chaperones and ERAD components and transiently reduces protein synthesis to decrease the burden on the ER. The process of ER stress response serves the interests of the HspA5 chaperone, and thus Ebola.


HspA5 is vital for Ebola replication
but when blocked, the growth of the
virus is halted under laboratory
conditions.


HspA5 Also Assists Viral Entry

The chaperone function of HspA5 is instrumental to the maturation of envelope proteins from a number of viruses, including the hepatitis C virus and influenza A virus. In addition to host protein chaperone function, HspA5 also plays a key role during viral infections. Aside from its role in protein folding, HspA5 also helps viruses enter into cells. Viruses so assisted include dengue fever.

HspA5 Chaperone Activity Essential for Ebola Infection

To determine HspA5’s essentiality for infection, the Army researchers utilized EGCG, a small polyphenol found in green tea. EGCG is an antioxidant phytochemical that prevents or neutralizes the damaging effects of free radicals. EGCG binds the ATP-binding site of HspA5, inhibiting its ability to bind ATP. Without ATPase** activity—ATP (adenosine triphosphate), aka the universal energy molecule in cells—HspA5 cannot perform its critical function as a protein chaperone, and proteins such as Ebola are not replicated.


* There are only 19 Biohazard Safety level-4 (BSL-4) bio-containment beds in the whole of the United States … and four in the UK. See more at: http://undergroundmedic.com/?p=6990#sthash.dGSu3X6M.dpuf

† Ribonucleic acid (RNA) is a polymeric molecule, implicated in the various biological roles in coding, decoding, regulation, and expression of genes.

‡ Deoxyribonucleic acid (DNA) is a molecule that encodes the genetic instructions used in the development and functioning of all known living organisms and many viruses.

§ A highly conserved gene is one that has a very similar sequence in different species—there has been evolutionary pressure not to change it. In other words, it is conserved.

** ATPases are a class of enzymes that catalyze the decomposition of ATP into ADP.


Figure 2 HspA5 (aka BiP) is a molecular chaperone located in the endoplasmic reticulum (ER) that binds newly synthesized proteins as they are translocated into the ER, and maintains them in a state competent for subsequent folding. If HspA5 is inhibited, as it can be by EGCG, proper folding cannot take place and proteins, such as Ebola, are not replicated, as contagion requires.

LEM1411_HspA5graph_274.gif
(click on thumbnail for full sized image)

In the study, an “immortal” cell line was treated with increasing concentrations of EGCG for 2 hours; then infected with Ebola. Forty-eight hours post-infection the cells were fixed and stained for Ebola infection. EGCG consistently exhibited a dose dependent inhibition of Ebola infection, indicating that HspA5 ATPase activity—and therefore chaperone function—is required for Ebola infection (see Fig. 2).

EGCG May Also Help Dengue Fever

Next, the Army team analyzed whether muting HspA5 expression influences Ebola protein production, as it appears to do in the case of dengue fever. Dengue fever is mosquito-borne and known in the U.S. through occasional outbreaks in Hawaii. The scientists transfected a specific cell line with either non-target (think placebo) or HspA5 transfectors before introducing Ebola. At 24 and 48 hours after infection, the researchers observed little impact on viral transcript production in cells infected with the non-target gene inhibitor.


An Ebola strand of RNA has been
described as pure information with
instructions for replication.


However, transfection of HspA5 produced a significant drop in viral transcript production at both time points. They also observed an increase at both time points (significantly at 48 hours) in HspA5 transcript levels, compared to uninfected samples. This indicates that Ebola infection upregulates the expression of HspA5, possibly through ER stress.

HspA5 Serves as an Entry Factor for Infection

The Army researchers also evaluated viral entry and exit. They found no link between HspA5 and Ebola entry using knockdown studies (when expression of one or more of an organism’s genes are reduced). However, they did note a novel role for HspA5—it increased viral budding. Then they once again introduced an Ebola viral matrix protein into the specific cell line, in both non-target and HspA5 gene inhibitors. After 48 hours, they isolated virus-like particles indicating decreased viral levels in the HspA5 samples. These data suggest that HSPA5 plays a novel role in viral budding (see the Export “budding” in Fig. 1).

The Mice Receiving Antisense Treatment Survived

Finally, the researchers examined in vivo targeting of HspA5 by antisense DNA nucleotide analogs previously demonstrated to be potentially antiviral. Antisense RNA is a single-stranded RNA that is complementary to a messenger RNA strand transcribed within a cell. They found that mice treated with HspA5-antisense DNA survived—negating the chaperone activity of HspA5—while the others succumbed to Ebola. The Fort Detrick team reports this to be the first in vivo, host-based gene targeting application using Ebola.

These data further support a critical role for HspA5 during Ebola infection. It is worth noting that prior Ebola antisense studies exclusively targeted viral transcripts.

Targeting HspA5 has an advantage over direct targeting of viral gene products, since the dependence on these factors makes development of escape mutants more difficult.

Additionally, the Fort Detrick research shows that there is greater potential to develop a broad spectrum therapeutic. In support of this, preliminary studies indicate targeting HspA5 also protects against the hemorrhagic Marburg virus infection (the data were not shown). As indicated earlier, these animal studies were performed in Fort Detrick’s containment labs, with biosafety level 4 (BSL-4) status, specified for working with Ebola.


EGCG consistently exhibited a dose
dependent inhibition of Ebola
infection
indicating that HspA5
ATPase activity and therefore
chaperone function is required for
Ebola infection.


Essential for Ebola Infection

The Army researchers went beyond their previous identification of HspA5 as an Ebola-associated host factor, and demonstrate that HspA5 is essential for Ebola infection. Targeting HspA5 both in vitro and in vivo resulted in significant reduction in virus replication and protection of mice against lethal virus challenge, respectively. Of crucial interest, a surrogate model for studying virus release using an Ebola viral matrix protein indicates that HspA5 is also required for budding. Therefore the researchers have identified a critical host factor for Ebola infection. Based on the current findings in this report, the Army researchers propose that HspA5 is a viable target for the development of anti-filovirus countermeasures.

Mere Aerosol or Airborne Transmission?

Some researchers who have studied Ebola worry that the repeated reassurance by the Center for Disease Control (CDC) and others about how Ebola is transmitted is misleading and counterproductive. C.J. Peters, MD, was director of a federal research center in Reston, VA, when an outbreak of Ebola killed research monkeys several years ago. Following this, he presided over research for the CDC to determine how the virus spreads. And this week, he told The Los Angeles Times that he “wouldn’t rule out” the possibility of airborne transmission in “tight quarters.”††


†† Willman D. Some Ebola experts worry virus may spread more easily than assumed. The Los Angeles Times. October 7, 2014. http://www.latimes.com/nation/la-na-ebola-questions-20141007-story.html#page=1. Accessed October 9, 2014.



The Fort Detrick team reports this to
be the first in vivo, host-based gene
targeting application using Ebola.


“Tight quarters” could certainly be construed as the interior of an airplane. Also worth noting, Dr. Peters doesn’t specifically contradict the CDC assertion that there is “zero risk of transmission” in such circumstances. As any careful researcher would say, “we just don’t have the data to exclude it.” Another Reston, VA researcher, Charles Baily, told the newspaper that the reassurance that the virus cannot be transmitted through the air is misleading because a cough or a sneeze of an infected person distributes mucus that is a bodily fluid. See subsection “Last Rites.”

The Great Worker Migration: Epidemic Explosive

A seasonal migration is about to begin in West Africa — even for young men whose villages have been recently hit by Ebola. The disease will likely spread in the months ahead, because the growing season is ending in October. When this happens each year, tens of thousands of young West African men and boys become part of a migratory work population not much different than U.S. migrant farm workers.

When the harvesting ends in Guinea, Sierra Leone, and Liberia, the migrant workers will head off for temporary jobs in nearby countries: gold mines, cocoa nut and palm oil plantations, palm date harvesting and fishing, and illicit charcoal production. The on foot treks usually last no longer than a few days, far shorter than the grace period before Ebola symptoms manifest. They needn’t use airplanes to move across Western Africa. Traveling by foot is sufficient.

Similar to many prior generations, they use little-known routes and detours through forests to avoid frontier checkpoints. Even so, they typically carry West African economic transit cards (ECOWAS) that ostensibly permit economic travel.

The Nightmare Scenario

Densely populated African cities swarming with jam-packed slums as far as the eye can see could be most at risk, creating a nightmare scenario. Sad to say, but there are no international, coordinated plans to deal with what would likely be an even more catastrophic event. Only, to the contrary, there is lots of bureaucratic bungling along with massive interference with market-based solutions. This virtually ensures that Plan A (local quarantine, etc.) will not work. Plan B does not currently exist. Finally, there is Plan C (safe vaccines; not available before Summer of 2015 at the earliest). While on the boards, this solution is tightly under government management—with, of course, little market steerage (there is money to be made and that is damnable!)—and thus will take longer, much longer, with less fruitful outcomes. Hundreds of thousands of people and perhaps more may die. We are screwed … unless we take the right type of actions now!

More Science about EGCG and Viruses

Durk Pearson & Sandy Shaw have written that, “A recent paper[7] reports on the antiviral effect of catechins in green tea on three different subtypes of influenza virus (including A/H1N1, the avian flu) in cell culture (MDCK, Madin-Darby canine kidney cells). EGCG (epigallocatechin ­gallate) was the most effective, completely inhibiting viral replication (detected by the release of new virus).” (See “Defending Yourself against Virus Infections” in the July 2009 issue). Also in that article, “The authors note that EGCG has been reported to be a “strong inhibitor” of HIV replication in cultured peripheral blood cells and to have antiviral activity against Epstein-Barr virus, as well as citing previous studies in which it has shown inhibition of influenza virus in cell cultures.” And there has been much more on anti-antiviral activity of EGCG since then (more than 260 articles to date in Pubmed).

Indeed, it is possible to design an antiviral supplement cocktail to ameliorate cytokine storms, which is the cause of death in Spanish, swine, and bird flus, and in the hemorrhagic fevers. Such a formulation might also contain high levels of vitamin D, which has been shown to be effective against Marburg, another hemorrhagic filovirus that involves the vitamin D receptor.

A New Meaning for Exponential

The latest data on the number of deaths caused by Ebola has just rolled in. According to the World Health Organization, the total as of October 8, 2014, is 4,013 individuals died out of 8,399 cases reported over seven months in seven countries.

Country by country deaths: 2,316 in Liberia, 930 in Sierra Leone, 778 in Guinea, eight in Nigeria—and one in the United States. Also, a separate Ebola outbreak in Democratic Republic of Congo has killed 43 people out of 71 cases.


The researchers found that mice
treated with HspA5-antisense DNA
survived—negating the chaperone
activity of HspA5—while the others
succumbed to Ebola.


Bear in mind that the statistics are widely estimated to be significantly under-reported, and that the actual case load to be as high as 20,000. Let’s say it is 10,000. If that is true, and the exponential (doubling) growth occurs every three weeks.

Ebola Week Ending Oct. 11, 2014 (10,000)

Ebola Week Ending Nov. 1, 2014 (20,000)

Ebola Week Ending Nov. 22, 2014 (40,000)

Ebola Week Ending Dec. 13, 2014 (80,000)

Ebola Week Ending Dec. 27, 2014 (160,000)

Ebola Week Ending Oct. 11, 2014 (320,000)

Ebola Week Ending Jan. 3, 2015 (640,000)

Ebola Week Ending Jan. 24, 2015 (1,280,000)

Ebola Week Ending Feb. 14, 2015 (2,560,000)

Ebola Week Ending Mar. 7, 2015 (5,120,000)

Ebola Week Ending Mar. 28, 2015 (10,240,000)

Ebola Week Ending Apr. 18, 2015 (20,480,000)

Ebola Week Ending May 9, 2015 (40,960,000)

Ebola Week Ending May 30, 2015 (81,920,000)

Ebola Week Ending Jun. 20, 2015 (163,840,000)

Ebola Week Ending Jul. 11, 2015 (527,680,000)

Ebola Week Ending Aug. 1, 2015 (655,360,000)

Ebola Week Ending Aug. 22, 2015 (1,310,720,000)

Ebola Week Ending Sep. 12, 2015 (2,621,440,000)

Ebola Week Ending Oct. 3, 2015 (5,242,880,000)

Ebola Week Ending Oct. 24, 2015 (The entire planet)

Meanwhile, the U.S. ambassador to the United Nations, Samantha Power (the wife of Cass Sunstein, who tends to believe that truth is a disease, if one can make sense of his statements), said Friday that Ebola infection rates are expected to climb.

To calm things down, Power said over at the U.N. General Assembly session on Ebola, October 10, 2014, “In Guinea and Sierra Leone, the number of infections is projected to double every month. In Liberia, infections are projected to double every two weeks [Emphasis added].”

Ebolaphobia

Is there too much concern about Ebola as demonstrated by the press playing on fear (354,000,000 hits in Google, while President Obama has 578,000,000 hits—so Ebola is closing in)? Indeed, there are several story lines.

The canine companion of the nurse diagnosed with Ebola in Madrid has just been killed and cremated by Spanish authorities.

Do dogs carry it? The authorities in Spain were taking no chances with Excalibur (the dog’s name). According to a recent scientific report, pigs and dogs can be infected with Ebola, but it is not known if they can transmit it.2 Nonetheless, the authorities just don’t know, but they must go through the motions of pretending that they know.

Spanish health workers expressed their anger with the government’s handling of an Ebola outbreak. They jeered at Prime Minister Mariano Rajoy, and bombarded his car with surgical gloves at a Madrid hospital where a nurse lay seriously ill with the virus. The nurse has since recovered.

Remember the skit from Monty Python and the Holy Grail, “We have found a witch. May we burn her?” Assuredly, there are no scientific studies not indicating that witches can’t transmit Ebola. However, in Sierra Leone in West Africa, some believe that Ebola is caused by witchcraft. Even governments believe that witches are the problem: Witchcraft is one of the top crimes in the Central African Republic, where around 40 percent of prosecutions involve witchcraft charges.


Targeting HspA5 has an advantage
over direct targeting of viral gene
products, since the dependence on
these factors makes development of
escape mutants more difficult.


President Obama has recently said that you can’t get Ebola from casual contact, like sitting next to someone on a bus. Two doctors in West Africa did and both were dead within one week. The CDC advises not to use public transportation.

From stiffing dogs and other inanities, the public is beginning to suspect that government bureaucrats who are in charge don’t know what they are doing.

By the way, this is true in most government endeavors, most of the time. Yet, the press does not cover these stories. So, we are not reminded of the degree of incompetence of our unlimited, faceless rulers. However, what is getting covered is the equivalent of the parable, The ­Emperor’s New Clothes. Yes, he has invisible clothing, and his staff and planners so believe in him that they are also wearing invisible clothing.

U.S. Case #2 and the Ministry of Truth

On Sunday, October 10, 2014 the head of the CDC announced that we have another case of Ebola in Dallas owing to a “breach of protocol.” This is also described as a hospital mistake. And after all those assurances that everything is under control.

Of significant interest, the female health worker infected was not on the most watched list because she had the worn the “full protective gear” of standard protocol, even though she had worked directly with Thomas Eric Duncan, the first victim who died on October 8. Furthermore, she was infected after he was admitted to Texas Health Presbyterian Hospital on Sept 28, when all workers were taking full precautions against Ebola transmission. You would imagine that the CDC would have been all over supervision of this patient, making sure that all protocols were being followed properly. Clearly, Ebola is here and may be vectoring. In fact, another nurse was diagnosed with Ebola in mid-October.

Is the CDC in control? Apparently not! Though they won’t admit it. Thus we have the “Ministry of Truth,” blaming it on the hospital, and probably, coming soon, the new victim. There had already been talk of suing Duncan.

Look on the Bright Side of Life

So there is at least one positive outcome of the Ebolaphobia, and that is the possibility that it will create a “distrust in government” epidemic. It has done this before, e.g., during the Black Death of 1348–50. Then, the public lost confidence in its rulers, civil as well as religious. Interestingly, some historians date the birth of the Renaissance with the decade of the 1350’s, a good thing.3

All of these nitwit government officials, hysterically running around, offering supposedly reassuring buzz phrases, are creating great skepticism among the populace. Here, there, and everywhere.

Melatonin Targets Ebola’s Pathological Changes


LEM4011endothelium-274.gif
(click on thumbnail for full sized image)

According to senior melatonin researcher, Russel Reiter, PhD, along with two other researchers, a new report has found that melatonin should have some practical utility as a treatment of the Ebola virus.1 Based on their extensive knowledge and experience with melatonin and understanding of the pathology of Ebola, the researchers strongly believe that melatonin has potential utility for use in the treatment of individuals who are infected with the Ebola virus. The pathological changes associated with an Ebola infection include: endothelial disruption, disseminated intravascular coagulation, and multiple organ hemorrhage. These are exactly the alterations that melatonin has been shown to target. The new report has high impact because Dr. Reiter is the Editor-in-Chief of the Journal of Pineal Research and on the Editorial Board of 7 other journals and the author of more than 1150 scientific articles listed in National Library of Medicine.


Researchers strongly believe that
melatonin has potential utility for
use in the treatment of individuals
who are infected with the Ebola
virus.


Many similarities between Ebola infection and septic shock have been recognized for at least ten years. Furthermore, melatonin has been successfully used for the treatment of sepsis in many experimental and clinical studies. Based on these factors — and since the number of treatments currently available is limited and the useable products are not abundant or available (such as ZMapp)—Reiter et al. encourage the use of melatonin for the treatment of Ebola virus infection. Melatonin has a high safety profile, is readily available, and can be orally self-administered; thus, the use of melatonin is compatible with the large scale of this serious outbreak.

Since melatonin has virtually no toxicity, along with conventional therapy, it would appear to have potential for treatment of Ebola viral infection, to reduce complications such as organ failure, bleeding and shock, and possibly could reduce the mortality rate.

Reference

  1. Tan DX, Reiter RJ, Manchester LC. Ebola virus disease: Potential use of melatonin as a treatment. J Pineal Res. 2014 Sep 27. doi: 10.1111/jpi.12186. [Epub ahead of print]

Last Rites

Despite the Emperor’s Clothing, the truth is that the Federal Government has no real plans to deal with Ebola. It has no theory to guide a plan. Attempting to calm the public, we get daily reports, which are mixed at best. For example, Ebola is not spread by airborne means—but if someone sneezes, transmission can occur. There are several studies showing that Ebola can be airborne. One, conducted recently, showed that piglets given Ebola and transferred to a room housing macaques monkeys infected all macaques without direct contact in an open inaccessible cage system.4 According to the researchers, this implicates a potential for airborne transmission of Ebola.

In another study, about a 1995 outbreak of Ebola in the Congo, researchers concluded that transmission occurred through airborne particles.5

Rethinking the Development of Ebola Treatments

From The Lancet we have a hot off the press opinion piece cautioning that, “If the global community is truly committed to rapidly developing a new drug for Ebola, multiple novel approaches, methods, and technologies will need to be used to beat the inherent hurdles of drug development.”‡‡ This means that unless the usual administrative protocol-lording is not changed (e.g., with the FDA), the antidote or vaccine will never be produced in time. Thus, the chances of the exponential curve that is so freighting may be greatly increased, Thus, the chances of the exponential curve that is so freighting may be greatly increased, and there will be more carriers to other countries.


‡‡ Gupta R. Rethinking the development of Ebola treatments. Lancet Glob Health. 2014 Oct;2(10):e563–4. doi: 10.1016/S2214–109X(14)70304–3.


The Ebola outbreak constitutes the “most severe acute health emergency in modern times,” warns the World Health Organization.6 Margaret Chan, the WHO’s director-general declared that the epidemic has proven that “the world is ill-prepared to respond to any severe, sustained, and threatening public health emergency.”

References

  1. Reid SP, Shurtleff AC, Costantino JA, Tritsch SR, Retterer C, Spurgers KB, Bavari S. HspA5 is an essential host factor for Ebola virus infection. Antiviral Res. 2014 Sep;109:171–4.
  2. Weingartl HM, Nfon C, Kobinger G. Review of Ebola virus infections in domestic animals. Dev Biol (Basel). 2013;135:211–8.
  3. North G. Drudge Takes Our Daily Temperature on Ebola. The Tea Party Economist. October 9, 2014. http://teapartyeconomist.com/2014/10/09/drudge-takes-daily-temperature-ebola/#AhBCTYboGUy3HQWA.99. Accessed October 9, 2014.
  4. Weingartl HM, Embury-Hyatt C, Nfon C, Leung A, Smith G, Kobinger G. Transmission of Ebola virus from pigs to non-human primates. Sci Rep. 2012;2:811.
  5. Roels TH, Bloom AS, Buffington J, Muhungu GL, Mac Kenzie WR, Khan AS, Ndambi R, Noah DL, Rolka HR, Peters CJ, Ksiazek TG. Ebola hemorrhagic fever, Kikwit, Democratic Republic of the Congo, 1995: risk factors for patients without a reported exposure. J Infect Dis. 1999 Feb;179 Suppl 1:S92–7.
  6. Watson L. WHO says Ebola is ‘most severe acute health emergency in modern times.’ The Telegraph. October, 13, 2014. http://www.telegraph.co.uk/news/worldnews/ebola/11158504/WHO-says-Ebola-is-most-severe-acute-health-emergency-in-modern-times.html. Accesssed October 13, 2014.
  7. Song JM, Lee KH, Seong BL. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res. 2005 Nov;68(2):66 – 74.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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