Wednesday, August 06, 2014

Ebola the Friendly Reaper


Ebola   the FRIENDLY Reaper .


Andre Willers
3 Aug 2014
Synopsis :
Like Tuberculosis , Ebola evolved to switch on lethality genes when conditions exceed a certain level of complexity . Complexity is ASSOCIATED with prosperity plus overpopulation . Gaian population control .
 
Discussion :
1.TB :
Briefly , TB co-evolved with humans . It is present in nearly everybody , but switches lethality genes on only in CERTAINcircumstances , usually related to shortages . Control of the lethality switches seems to be another layer of controls above the Epigenetic system .
 
2. Complexity :
Note how complexity enables the lethality switch-on

 3. Epidemics without pathogens .
Repeated in Appendix IV .
 
4. How does complexity benefit an extremely lethal organism like Ebola ?
Complexity can be MEASURED by the level of the Network of the hosts
In a simple society  , the disease burns out QUICKLY and is self-containing . Lethality genes have evolved not to switch on .
But when things get more complicated , Small-World Networks develop , with Hierarchies that enables small groups to prosper and TRAVEL .
 Long-distance links enables organisms with long infectious , symptom FREE  progress to prosper by infecting many hosts .
Quorum MECHANISMS switch on lethality genes .
 
 5. Pneumonic Ebola can then be expected to switch on .
It already exists .
Abstract
In 2008, Reston ebolavirus (REBOV) was isolated from pigs during a disease INVESTIGATION in the Philippines. Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV-2) infections were also confirmed in affected herds and the contribution of REBOV to the disease outbreak remains uncertain. We have conducted experimental challenge studies in 5-week-old pigs, with exposure of animals to 106 TCID50 of a 2008 swine isolate of REBOV via either the oronasal or subcutaneous route. Replication of virus in internal organs and viral shedding from the nasopharynx were documented in the absence of clinical SIGNS of disease in infected pigs. These observations confirm not only that asymptomatic infection of pigs with REBOV occurs, but that animals so affected pose a transmission risk to farm, veterinary, and abattoir workers.
……………………………………………………………………………………………………………………………………………………………………………………………………………………………….
 
6.Quarantine :
Quarantine collapses the Small-World Network . Virulence should decrease .
You wonder whether you would STAND a better chance inside a quarantined zone than outside .
Things are much less complicated inside the quarantine zone . Will some of the lethality genes STAND down ?
Any VOLUNTEERS to find out ?
There should be some way of getting such DATA for Cholera , Spanish Flu , Flu , etc .
 
7.Is there any hope ?
YES , but only off-planet .
Homo Sapiens’s greed and stupidity have pushed the systems very far out of balance .
The plagues and the eco-disturbances are survivable , but most of the damage will be done by warfare .
 
And of course , that old chestnut “The SINGULARITY.”
Which seems SINGULARLY absent .
Like a quantum-spin DIVORCING it’s parent-particle .
 
COUGHING is Capital Offence !”
Andre
 
Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Appendix I
A pop version of http://www.ncbi.nlm.nih.gov/pubmed/24590073 . (For full version , see Appendix II below .)

8/3/2014 A Possible Cure for Ebola Virus Infection? | RealClearScience

RealClearScience Journal Club
SCIENCE Figures Interpreted and Analyzed by RealClearScience
A Possible Cure for Ebola Virus Infection?
By Alex B. Berezow - April 21, 2014

Ebola is one of the scariest viruses on Earth. Along with Marburg and a few other lesser known viruses, it is
a member of the Filoviridae FAMILY, a nasty group of microbes that causes hemorrhagic fever. Like most
viral diseases, patients with hemorrhagic fever will first present with flu-like symptoms. As the disease
progresses, patients often bleed from their body orifices, such as their eyes and ears. Death, however, does
not result from blood loss, but from shock or organ failure.

Hemorrhagic fevers are not easy to catch. Transmission generally requires prolonged contact with the
patient or with his bodily fluids. Mortality rates depend on the particular viral strain. For Ebola, the
deadliest strain is Zaire, which can kill up to 90% of those infected. The worst ever outbreak occurred in
Congo in 1976. That year, 318 PEOPLE were infected and 280 died, a mortality rate of 88%. Currently, an
outbreak of Ebola has killed at least 135 people in west Africa. The virus resembles Zaire, but researchers
have determined that it is a brand new strain.

Obviously, finding a treatment or cure for such a
frightening disease is desirable. With our HIGHLY
interconnected world, it is only a matter of time BEFORE a hemorrhagic fever shows up on our doorstep.
(Actually, that's already happened.) Unfortunately, at the present time, there is little that can be DONE for a
victim of Ebola or any other hemorrhagic fever. Mostly, patients are kept hydrated and symptoms are
treated as they arise. Other than that, doctors CROSS their fingers and hope the patient doesn't die.
That may be about to change. In the journal Nature, scientists -- whoCONDUCTED much of their work in the
secretive, high-containment biological laboratory maintained by USAMRIID at Fort Detrick, Maryland --
have reported the discovery of a SMALL molecule that rescues rodents and monkeys from various



8/3/2014 A POSSIBLE Cure for Ebola Virus Infection? | RealClearScience

hemorrhagic fevers. Even more, the drug EXHIBITED activity against a wide range of viruses.
The molecule, named BCX4430, resembles the famous "A" found in DNA: adenosine. (Recall that DNA is
made of Adenosine, Thymidine, Cytidine and Guanosine.) The RNA-based filoviruses also use "A" in their
genomes. BCX4430, because it resembles "A", can be accidentally used by the virus when it is trying to
grow inside of our cells. For the virus, this is a fatal mistake. BCX4430 blocks further growth and
reproduction.
Hold up a minute, you're probably thinking. DON'T all cells use "A" too? Shouldn't this drug be expected to
hurt not only the virus, but humans as well? That would be a reasonable expectation, but for some reason,
BCX4430 APPEARS to only hurt the virus. Human cells appear not to be fooled by BCX4430 and do just
fine in its presence.
The most compelling experiment the research team ran involved the infection of cynomolgus macaque
monkeys with deadly Marburg virus. Macaques were given twice daily doses of BCX4430 for 14 days
beginning 1 hour, 24 hours, or 48 hours post-infection. (See graph. There were six monkeys in each
treatment GROUP.)
As shown above, all of the monkeys that did not receive BCX4430 (LABELED "vehicle") died by day 12.
However, every monkey (EXCEPT for one) that received a dose of BCX4430 survived, even if the initial
dose came 48 hours after infection. In total, 17 out of 18 treated monkeys lived.
Amazingly, in vitro experiments showed that BCX4430 could potentially work AGAINST a wide range of
viruses, including SARS, MERS, influenza, dengue, and measles.
Because no human CLINICAL TRIALS have yet been conducted, it's still far too early to pop the cork on our
champagne bottle. But this antiviral HOLDS the greatest potential for curing nightmarish hemorrhagic
fevers.
Source: TK Warren et al. "Protection against filovirus diseases by a novel broad-spectrum nucleoside
analogue BCX4430." Nature 508: 402-405 (2014). doi:10.1038/nature13027


xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Appendix II
Nature. 2014 Apr 17;508(7496):402-5. doi: 10.1038/nature13027. Epub 2014 Mar 2.
Protection AGAINST filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430.
·         1Division of Molecular and Translational SCIENCES, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
·         2BioCryst Pharmaceuticals Inc., Durham, NORTH Carolina 27703, USA.
·         31] BioCryst Pharmaceuticals Inc., Durham, NORTH Carolina 27703, USA [2] Wilco Consulting, LLC, Durham, North Carolina 27712, USA.
·         4MedExpert Consulting, Inc., Indialantic, Florida 32903, USA.
Abstract
Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 COMPLETELY protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.
Comment in
·         Antiviral drugs: Spanner in the works of filovirus infection. [Nat Rev Drug Discov. 2014]
·         Possible leap ahead in filovirus therapeutics. [Cell Res. 2014]
Xxxxxxxxxxxxxxxxxxxxxxxxxx
Appendix III
Similar molecules mimicking nucleotides in DNA or RNA can throw a spanner in the works .
Examples :
1)
Thymine          5-Bromouracil ( web.stanford.edu/~kendric/PDF/A16.pdf) . Taken up into DNA , it makes organism more sensitive to UV .
 
2) FORCED mutations



Tuesday, July 29, 2014

FORCED MUTATIONS

Fifteen years ago, MIT professor John Essigmann and colleagues from the University of Washington had a novel idea for an HIV drug. They thought if they could induce the virus to mutate uncontrollably, they could FORCE it to weaken and eventually die out — a strategy that our immune system uses against many viruses.

The researchers developed such a drug, which caused HIV to mutate at an enhanced rate, as expected. But it did not eliminate the virus from patients in a small CLINICAL TRIALreported in 2011. In a new study, however, Essigmann and colleagues have determined the mechanism behind the drug’s action, which they believe could help them develop better versions that would destroy the virus more quickly.

This type of drug could, they say, HELP combat the residual virus that remains in the T cells of patients whose disease has been brought into long-term remission by the triple-drug combination typically used to treat HIV. These viruses re-emerge periodically, which is why patients must stay on the drug cocktail indefinitely and are not considered “cured.”

“This has really been the biggest problem in HIV,” says Essigmann, the William R. and Betsy P. Leitch Professor of Chemistry, Toxicology, and Biological Engineering at MIT. “What we would hope is that over a long period of time on this type of therapy, a PERSON would potentially have their latent pool mutated to the extent that it no longer causes active disease.”

In the new study, which appears in the Proceedings of the National Academy of SCIENCES (PNAS) the week of July 28, the researchers discovered exactly how the drug, known as KP1212, induces the HIV genome to mutate. The paper’s lead authors are MIT postdocs Deyu Li, Bogdan Fedeles, and Vipender Singh, along with recent MIT PhD graduate Chunte Sam Peng. Essigmann and Andrei Tokmakoff, a former MIT professor who is now at the University of Chicago, are the paper’s senior authors.


Too MUCH mutation

After HIV INFECTS a cell, it rapidly begins making copies of its genetic material. This copying is very error-prone, so the virus mutates swiftly. This usually helps the virus survive by allowing it to evade both the immune system and human-made drugs. However, at a conference in the late 1990s, Essigmann learned from an evolutionary biologist that if the virus could be forced to double its mutation rate, it would no longer be able to produce functional proteins.

Essigmann and Lawrence Loeb, a professor of biochemistry at the University of Washington, started working together to exploit this idea. Essigmann had been developing compounds that mimic natural nucleotides — the A, C, T, and G “LETTERS” that form DNA base pairs — but that induce genetic mutations by binding with the wrong partner.   Loeb is an expert on polymerases, the enzymes that string nucleotides together to form DNA or RNA.

Together with James Mullins, an immunology professor and HIV expert at the University of Washington, Essigmann and Loeb designed a molecule called 5-hydroxycytosine, described in a 1999 PNAS PAPER. When given to HIV-infected cells grown in the lab, this molecule was incorporated into the viral genome in place of the natural form of cytosine. Within 25 viral replication cycles, HIV populations in those infected cells collapsed.

The researchers then formed a company, Koronis Pharmaceuticals, which developed KP1212, a compound that is 100 times more mutagenic than 5-hydroxycytosine. In a four-month CLINICAL TRIAL of 32 patients, mutations accumulated in the patients’ viral DNA, but not enough to induce a population crash. The drug was also found to be safe: It did not mutate the patients’ own DNA, in part because the drug was designed so that human forms of DNA polymerase could not accept it.


SHAPE-shifting molecules

In the new PNAS paper, the researchers used advanced spectroscopy techniques to analyze KP1212’s ability to promote tautomerism, a chemical phenomenon that involves the migration of protons among the nitrogen and oxygen atoms on nucleic-acid bases. This allowed the researchers to see that ONCE KP1212 inserts itself into the genome, it can switch among five different shapes, or tautomers. Some of these behave like cytosine, by pairing with guanine. However, some of the tautomers resemble thymine, so they will pair with adenine, introducing mutations.

“The five molecules are changing shape on a nanosecond timescale, and each shape has a different base-pairing property, so you will see a promiscuity in terms of the bases with which KP1212 pairs,” Singh says.

To see this shape-shifting, the researchers used NMR and a form of 2-D infrared spectroscopy developed by Tokmakoff. This technology ALLOWS scientists to determine the atomic composition and structure of nucleic-acid bases.

Then, using a genetic tool DEVELOPED in the Essigmann lab, the researchers determined that KP1212 induces a mutation rate of exactly 10 percent in the HIV genome. Based on these findings, Essigmann estimates that if KP1212 doubles the mutation rate of HIV, it could clear the virus from patients in one to two years.

He says that Koronis hopes to run a longer trial of KP1212 and is also INTERESTED in developing drugs that would work faster, which could be accomplished by altering some of the chemical features of the molecule and testing whether they speed up the mutation rate.

“This technology allows you to detect the quantitative contribution of different tautomers to the types and frequencies of mispairing by nucleoside analogs,” says Loeb, who was not involved in the new paper. “It would ALLOW you to test ahead of time what is making the mispairing occur with the compound that you’re using.”

The paper also identified other FACTORS that scientists could manipulate to improve the drug’s performance.

“There are other variables that are important to calculate the TIME it would take to eradicate a virus,” Fedeles says. “That includes the concentration that the drug needs to achieve inside the cell, and the ability of a cell to convert the nucleoside, the molecule without the phosphate, to the triphosphate version, which is the one incorporated by the polymerase.”

“We’re building up a new strategy that can give us a lot of insights into how to design a new molecule,” Li says. “It’s a new toolset for developing FUTURE drugs. Those drugs are not limited to HIV. They could be candidates for dengue fever, or some other viruses such as yellow fever.”

Ribavirin, a drug used to treat hepatitis C, and the influenza drug T-705 are also believed to provoke hypermutation in their target viruses. The MIT team also plans to work with Loeb to test the POSSIBILITY of using similar compounds to force tumor cells to mutate themselves into extinction.

The research was funded by the National Institutes of Health, the National Science FOUNDATION, and the MIT Laser Biomedical Research Center.

Posted by Basil Venitis at 3:14 PM 
Xxxxxxxxxxxxxxxxxxxxxxxx

Thursday, October 28, 2010
Epidemics without Pathogen transmission .
Epidemics without Pathogen transmission .
Andre Willers
28 Oct 2010

Synopsis:
Epidemics can manifest without pathogen transmission if (1) pathogens are already present in an organism , but with lethality genes switched off , and (2) quorum markers can be transmitted .

Discussion:
This has not been much of a problem as yet , because we did not have filters good enough to keep out bacteriological (maybe even viral) particles . But we do now . Nano filters (eg Uni Stellenbosch simple and cheap WATER FILTER using tangled bundles of carbon nano-fibres) .

This will keep out the nasty , large bugs , but not the marker molecules used to transmit information in the bacterial/viral quorum system .

Everybody has endogenous potentially harmful bacteria . But their lethality genes are switched off as long as they are better off in a healthy host .

For example , the water might test clear of any pathogen , but have a high enough concentration of quorum markers to trigger the lethality switches of endogenous bacteria or viruses .
They then SEND out more markers . If there is a shared medium like water , a ripple of bacterial activation is sent out . This can have a positive feedback if the water supply is limited , concentrating the markers .

Urine:
And , of course nothing concentrates the markers more than urine .
So , urine might test sterile , but still kill you stone dead by activating lethality switches .

That will teach you to pee in the pool !

Note the decreased mortality due to male circumcision . Less urine is retained in the prepuce . The same effect is observed in females with tampons and pads , or in general with nappies . A form of anaphylactic shock , as the lethality genes get quorum , switch on and the body's immune system responds . But the little buggers are all over , so the immune system tries to respond all-over , instead of localized (which is it's forte) . This is anaphylactic , systemic shock . A variant is known as asthma .

Prophylactic MEASURES :
1.Keep pubic hairs short
See http://andreswhy.blogspot.com "Old Age markers" 23 Dec 2007
This is to prevent quorum markers from sticking around . A bidet with CLEAN WATER is recommended .
2.Use some toilet PAPER . Nothing soggy or wet should be retained in contact with the body .
Do not use absorbent underwear .The longer it stays wet , the longer it zaps you .

Some other horries:

1.Flesh eating bacteria . A "tragedy of the commons" variant . The bacteria get a quorum telling them that the host is dead or in extremis . They promptly switch on genes that enable them to eat the host .

2.Cancers . Some types of cancers are similar .

3.Consumptive type diseases : by definition .

4.Air-borne quorum markers .
Possible , but would normally be limited to the personal heat-envelope . If this is a problem , use a simple fan . Will be a problem in space-habitats . TB?

5.Touch quorum markers (includes fluid exchange)
The HIV to AIDS transition springs to mind . Many people live quite happily with HIV even without ARV's , but something triggers the quorum mechanism and the lethality RNA switches on . This suggests a very low quorum .
Our venerable history of Democracy suggests two solutions : kill the voters (ie quorum markers) or saturate with shills . This second has been found most effective .

This MEANS :
Accellerate the HIV mutation rate . Flood the system with their marker products (about a cc injection) .
This will prevent a quorum . It will also make the Pharma's happy , as it means a repeated dose is necessary .

The usual human choice .
Pay up or die .

Andre


xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Appendix Images
NOTE similar chemical structures :

BCX4430



Additional Products to Explore







xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx


No comments: