Phage , the virus that cures

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It's a complicated spectrum. Technically, symbiosis does not require that both organisms benefit; parasitic relationships are symbiotic, for example. However, I wouldn't even say that human relationships with parasites are purely parasitic; I reckon that intermittent diarrhoea is a small price to pay for not having Crohn's disease. There is a small risk of malnutrition with worms, because they do, as you say, absorb nutrients before we get a chance to. However, again. That's a small price to pay if the alternative is Crohn's disease.

But yes, sometimes the organisms used are the same that cause pathological infection in humans. I initially read about pig whipworm being used to treat Crohn's, but it appears that other species seem to work as well, such as hookworms, and for other autoimmune diseases too.
Interesting.
But what is the cause of Crohn's disease ? And what do these worms do ?
Thinking that these worms are parasites, would mean that these worms benefit to no be attacked by the immune system of the host. Thus i can assume, that these worm have all these biochemicals to suppress the immune system. Thus not attacking the real cause of Crohn's disease ?

Another possibility may be that the worm has biochemicals that attack or suppress certain bacteria or fungi or maybe even other parasites. It makes me think of single celled organisms that can also be parasites.
Thus in this case attacking the real cause of Crohn's disease ?

Has there been research done to find out why these nematodes seem so beneficial ? I can imagine that the intestines is not really a friendly place to live in. Thus it makes sense that parasitic worms have a whole range of biochemicals to defend themselves from being food or getting infected or attacked themselves...

The way nature works, it is hard for me to believe that nature works just by a single infection vector. The few cases we managed to solve such as smallpox, is rare and definitely not the standard.
Almost all disease happen because of a multitude of infection vectors. Multiple different pathogens. continuous exposure to low amounts of toxins. And sometimes a little bit of genetics. It is the cause of many diseases.
 
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Mr. Pedantic

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Interesting.
But what is the cause of Crohn's disease ? And what do these worms do ?
Thinking that these worms are parasites, would mean that these worms benefit to no be attacked by the immune system of the host. Thus i can assume, that these worm have all these biochemicals to suppress the immune system. Thus not attacking the real cause of Crohn's disease ?

Another possibility may be that the worm has biochemicals that attack or suppress certain bacteria or fungi or maybe even other parasites. It makes me think of single celled organisms that can also be parasites.
Thus in this case attacking the real cause of Crohn's disease ?

Has there been research done to find out why these nematodes seem so beneficial ? I can imagine that the intestines is not really a friendly place to live in. Thus it makes sense that parasitic worms have a whole range of biochemicals to defend themselves from being food or getting infected or attacked themselves...

The way nature works, it is hard for me to believe that nature works just by a single infection vector. The few cases we managed to solve such as smallpox, is rare and definitely not the standard.
Almost all disease happen because of a multitude of infection vectors. Multiple different pathogens. continuous exposure to low amounts of toxins. And sometimes a little bit of genetics. It is the cause of many diseases.
The cause of Crohn's disease is not entirely known. More recently, it is thought that the disease is due to an overactive adaptive immune system to compensate for a dysfunctional innate immune system. The idea behind this is that there are two different immune systems in the body.

The innate immune system is responsible for most inflammatory responses in the body. Cells in the body contain certain markers known as cytokines, that are released when they are subjected to abnormal conditions - heat, cold, physical trauma, hypoxia, etc. When these are released, neutrophils and macrophages nearby migrate towards the site and begin cleaning up the area by ingesting debris (for this reason, they are known as phagocytes - literally, cells that eat).They cause an inflammatory response designed to kill off cells too damaged to repair, help cells that can be repaired, and helping rebuild the damaged tissue. The inflammatory response also induces swelling, which increases lymphatic drainage from the area and therefore increases recognition of bacteria for the adaptive immune system in the lymph nodes. It's more complicated than this, but this is the general gist of it. One thing of interest to note with regard to what we are talking about is that there is a type of cell known as an eosinophil, which is also recruited as part of the inflammatory response, and its specialist role is to fight off multicellular parasites by secreting histamines and not killing the parasite so much as making its environment so unpleasant that it abandons its place in search of a more habitable location.

The adaptive immune system is composed of two major cell lines, as well as many less major ones (but still very important). The two major lines are B and T cells. B cells, simply put, produce antibodies. T cells are divided into Helper T cells and Cytotoxic T cells. Cytotoxic T cells specialize in destroying the body's own cells (e.g. if they are cancerous, or if they are host to viral infection), whereas Helper T cells regulate and manage the immune response. The Helper T-cell role is shared by most of the other immune cells in the body, for the Helper T cell that is their main role.

Continuing on with the inflammatory response, if there are bacteria, they are eaten up by antigen presenting cells. It's complicated, and it turns out that most cells in the body can perform some antigen-presenting role, but the main ones are macrophages and dendritic cells, which are composed largely of dendrites (they look a bit like neurons) to increase the tissue volume they can cover. These ingest pathogens, and present their protein fragments on the cell membrane. They then go on a tour of the body's lymph nodes trying to find T- and B-cells that will react to the fragments. Once they do, those B- and T-cells are activated. The B-cells produce antibodies that bind to the protein fragments on live bacteria, marking them for destruction, and the T-cells destroy and clean up cells that have the fragments on their cell membranes, and modulate the immune response.

The whole thing is more complicated than this, and there are other cells that share T-cell functions, as well as natural killer cells. But they're not so important to this discussion.

So going back to the beginning, the colon is a dirty place - it's colonized with more bacteria than there are human cells in the body. In normal people, the innate immune system performs a vital role in preventing any of them from actually getting into the bloodstream, and causing bacteraemia and sepsis. The adaptive immune system helps as well, but the job is first and foremost performed by the innate immune system. In people with Crohn's, for some reason or another it's thought the cytokine signalling doesn't work as well as it should, and bacteria get down to the level where the adaptive immune system has to compensate. Partly because of the bacterial infection, and partly because of the immune system's response to such, the result is inflammation of parts of the large bowel. This causes the symptoms of Crohn's - pain, bloating, diarrhoea/constipation (sometimes in the same day), etc. Not pleasant.

The idea with introducing parasites is that it provides an actual pathogenic infection in the gut. The normal bacteria that colonize the bowel are for the large part, harmless normally and there is a certain degree of tolerance inbuilt into the immune system from birth (the bacteria are actually in the bowel before the body's immune system is built up enough to recognize it properly). Whereas parasites are something wholly foreign and therefore, need to be expelled. This is thought to kickstart the innate immune system into actually doing its job - the bacteria are brought back into line, total inflammation goes down, and symptoms go away.

In some people, of course, parasitic infections come with their own symptoms - diarrhoea being the main one as far as I know. However, this is generally a much better state of affairs for someone with inflammatory bowel diseases than their inflammatory bowel disease. Of course, there are other autoimmune diseases where parasites have been trialled to some success, such as multiple sclerosis.

To answer your other question, yes, the worms do cause a bit of immune suppression. But the mainstay of treatment of autoimmune diseases is immunosuppression anyway - azathioprine and methotrexate, as well as steroids - so even if parasite benefit were restricted to immunosuppression, it would still be a viable option.

And you are right, Crohn's disease is partly genetic, partly environmental. For example, vegetarians seem to have some protective benefit from Crohn's, smokers are protected from ulcerative colitis, etc. But a large portion of Crohn's is genetic as well.
 
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Interesting. There is something that i had to think immediately after i read it.
Macrophages. Often macrophages are found in fatty tissue that is known to become cancerous ?
I have seen a few times macrophages noted in cancer research. What if the following scenario would happen : A macrophage engulfs a pathogen. But the pathogen does not die. What would happen ? would it take over the macrophage ? Imagine a macrophage consuming a cell filled with fresh new viruses ?
Migrating towards fatty tissue.
 
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Thinking of genetics and protection against diseases : Alkaloids.


There is something that striked me before. I knew people who where long term addicts. Some only used the smokable form of cocaine. And just as some cigarette smokers who seem to be genetically able to harness the effects of nicotine and almost never get sick or even cancer or acquire auto immune diseases, some of these cocaine smokers seem to have the same effect. Most will die, from some sort of disease but some exception seem to have a high tolerance for cocaine and even enjoying . They still live the life of a typical addict but they hardly ever get sick while having an extremely stressful life, hardly any sleep, hardly a healthy diet.
Yet, no auto immune diseases. Rarely get sick physically, at least not more then one might expect when thinking of the lifestyle. No more then an individual who lives a humble life.
I am not promoting it here. Not at all. I discourage the use of such chemicals. But i am curious what is the scientific explanation here...

Now nicotine is a toxin produced by plants.
Caffeine is also known for to be toxic or to prevent competition from other plants.
Cocaine is also used by plants as a measure of protection.
Alkaloids, how could these directly influence a persons immune system ?
I can only think of an indirect way by modulating corticoid production.
 
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To expand further -

T helper cells can be divided into two categories (actually more, but let's simplify) based on the kind of response they cause, TH1 and TH2.

A TH1 response is sometime called a 'cell mediated' response, because strong activation of macrophages and NK cells is one hallmark. Antibodies are produced, but not at especially high levels. It tends to cause a lot of inflammation which can cause tissue damage in high amounts or over long periods of time. TH1 T cell secrete (among other things) interferon gamma, a pro inflammatory cytokine a strong activator of Macrophages, NK cells, and an inhibitor of TH2 cells.

TH2 responses are sometimes called 'humoral' responses, the response is noted by a strong activation of B cells and thus lots of antibody production. Basophils and eosinophils can also be activated. TH2 cells produce (among other things) IL4 and IL10, both of which promote B cells switching to IgG and sometimes IgE. Both are considered anti inflammatory, they also inhibit TH1 cells. Or - part of the reason they are anti inflammatory is they inhibit TH1 cells.

A few general (not universally true) ideas - response to many disease starts as TH1, then eventually switches over to TH2. A Th1 response is needed against intracellular pathogens. A Th2 response is preferred (maybe needed) against parasites (IgE is considered to be an antiparasitic specialist antibody).

Crohn's disease shows some aspects of a TH1 response, including macrophage involvement (It might actually be TH17, but my overall idea might still hold). So - maybe what the worms are doing is stimulating a set of TH2 cells, which then inhibit the inflammation seen in Crohn's.
 
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A macrophage engulfs a pathogen. But the pathogen does not die. What would happen ?
This happens pretty frequently in tuberculosis (some other diseases too). Macrophage dies, eventually bursting and releasing a bunch of bacteria.
 

Mr. Pedantic

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Interesting. There is something that i had to think immediately after i read it.
Macrophages. Often macrophages are found in fatty tissue that is known to become cancerous ?
I have seen a few times macrophages noted in cancer research. What if the following scenario would happen : A macrophage engulfs a pathogen. But the pathogen does not die. What would happen ? would it take over the macrophage ? Imagine a macrophage consuming a cell filled with fresh new viruses ?
Migrating towards fatty tissue.
That actually happens in TB. M. tuberculosis gets inhaled, gets down into alveoli, and invades the alveolar macrophages that try to engulf it. It then replicates and eventually kills the macrophage. TB is a very interesting disease.

S. aureus also has some capability like this; instead of replicating, however, it just kills the phagocyte.

Macrophages are just one of the body's cells. They are implicated in many pathologies, such as atherosclerosis, because these pathologies are related to the formation of things that macrophages try to ingest, but can't. But generally, macrophages are involved in almost all inflammatory responses in the body (and cancer can cause an inflammatory response). They're more important in chronic inflammation than neutrophils because they live a lot longer, and because they have more functions as well in terms of signalling and immune mediating, it is logical that they would have a larger role to play in disease.
 
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That actually happens in TB. M. tuberculosis gets inhaled, gets down into alveoli, and invades the alveolar macrophages that try to engulf it. It then replicates and eventually kills the macrophage. TB is a very interesting disease.

S. aureus also has some capability like this; instead of replicating, however, it just kills the phagocyte.

Macrophages are just one of the body's cells. They are implicated in many pathologies, such as atherosclerosis, because these pathologies are related to the formation of things that macrophages try to ingest, but can't. But generally, macrophages are involved in almost all inflammatory responses in the body (and cancer can cause an inflammatory response). They're more important in chronic inflammation than neutrophils because they live a lot longer, and because they have more functions as well in terms of signalling and immune mediating, it is logical that they would have a larger role to play in disease.
Nature never ceases to amaze me...
 
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It sure is. And i love it all.

Taking cool literally, i shall poetically write these words :
*Think of hearing a voice similar of Ian McDiarmid but as an electrical plasma being modulated.

"
Just when i once thought that interstellar space was cold in a universe...
Out side a universe, cool and cold really has a rather new meaning.
Hell being hot ? Humbug...
It is the cold constantly consuming my energy that was hell...
But i would never die... Because there exist no time...
A universe is such a bliss. A heaven it is.
Having a beginning and an end. Something in between.
Never allow it to cease to exist before the required rebirth...
Just as there is the Gaia hypothesis of planet earth in this small solar system...
Give the universe a reason to exist...
"
 
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Mr. Pedantic

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Feb 14, 2010
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To expand further -

T helper cells can be divided into two categories (actually more, but let's simplify) based on the kind of response they cause, TH1 and TH2.

A TH1 response is sometime called a 'cell mediated' response, because strong activation of macrophages and NK cells is one hallmark. Antibodies are produced, but not at especially high levels. It tends to cause a lot of inflammation which can cause tissue damage in high amounts or over long periods of time. TH1 T cell secrete (among other things) interferon gamma, a pro inflammatory cytokine a strong activator of Macrophages, NK cells, and an inhibitor of TH2 cells.

TH2 responses are sometimes called 'humoral' responses, the response is noted by a strong activation of B cells and thus lots of antibody production. Basophils and eosinophils can also be activated. TH2 cells produce (among other things) IL4 and IL10, both of which promote B cells switching to IgG and sometimes IgE. Both are considered anti inflammatory, they also inhibit TH1 cells. Or - part of the reason they are anti inflammatory is they inhibit TH1 cells.

A few general (not universally true) ideas - response to many disease starts as TH1, then eventually switches over to TH2. A Th1 response is needed against intracellular pathogens. A Th2 response is preferred (maybe needed) against parasites (IgE is considered to be an antiparasitic specialist antibody).

Crohn's disease shows some aspects of a TH1 response, including macrophage involvement (It might actually be TH17, but my overall idea might still hold). So - maybe what the worms are doing is stimulating a set of TH2 cells, which then inhibit the inflammation seen in Crohn's.
Thanks :) I know I'm not great at immunology (still)
 
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Mr pedantic & gibsons:thumbsup:, thank you for the detailed posts. I am enjoying the posts a lot.:thumbsup: I now am going to watch 4 horror movies in a row. And give comments together with all other viewers .:biggrin:
 
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A nice bacteriophage animation :


You might have to click on the picture.
 
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More about bacteria that can almost halt their metabolism :
These bacteria are estimated to thousands of year old and maybe older according to the researchers. But what is most striking is the ability of these bacteria to make use with an absolute minimum of energy to stay functional : Alive.

http://phys.org/news/2012-05-bacteria-alive-million-year-old-seabed-clay.html

(Phys.org) -- A new study by scientists from Denmark and Germany has found live bacteria trapped in red clay deposited on the ocean floor some 86 million years ago. The bacteria use miniscule amounts of oxygen and move only extremely slowly.

Researchers led by Hans Røy from the Center for Geomicrobiology at Aarhus University in Denmark, extracted samples from columns of sediment up to around 30 meters beneath the sea floor in the region of rotating currents north of Hawaii known as the North Pacific Gyre. The sediment columns, built up by deposition of clay, dead algae and crustaceans, and dust, can be as much as several kilometres thick, with the most ancient sediment at the bottom of the columns.

The team used sensitive oxygen sensors to measure the oxygen concentration in the sediment cores. Knowing how much oxygen should have been present at each level allowed them to determine if oxygen was “missing,” which meant it had been consumed by microbes. In most regions of seabed examined previously, all the oxygen is consumed within the first 10 cm of sediment.

They discovered that bacteria within the clay were slowly using the oxygen, and remained alive even at a depth of around 30 meters, even though they have not had access to fresh organic matter for millions of years.

Oxygen respiration rates at the sediment-water interface were 10 μM per liter of sediment per year, and dropped to 0.001 μM at 30 meters, where the sediments were estimated to be 86 million years old. Cellular respiration rates also decreased with depth but stabilized at 0.001 femtomoles of oxygen per cell per day at 1.10 meters beneath the sea floor. (A femtomole is a billionth of a millionth of a mole.) Røy said the team had “no clue” how the microbes were able to subsist on so little oxygen.

Dr. Røy’s team estimated the turnover of the bacterial biomass would take from a few hundred to a few thousand years, but the turnover could represent cell repair rather than cell division. The bacteria may be operating on the absolute minimum energy requirement, which is just sufficient to keep their DNA and enzymes working, and to maintain an electric potential across their cell membranes.

The activity of the bacteria is so slow that Røy likened it to staring at a tree to watch it grow taller, and said the team did not know if the bacteria were reproducing, or if they were the same bacteria that had been deposited in the sediment and were “just not dying.” He estimated they must be at least 1000 years old, but could be much older. They have no contact with sunlight or the surface.


Røy said that an estimated 90 percent of the Earth’s microbial life may exist under the sea floor, but studying them was difficult because the methods have been developed in studying bacteria with rapid life-cycles.

Dr Røy said similar life forms could exist on other planets; if microbial life had ever existed, they could remain alive even if cut off from the surface for millions of years. He also said it gave him a greater appreciation of life on Earth, that you can store clay on the bottom of the sea for 86 million years and find that “somebody’s still living in it.”

More information: Aerobic Microbial Respiration in 86-Million-Year-Old Deep-Sea Red Clay, Science 18 May 2012: Vol. 336 no. 6083 pp. 922-925. DOI: 10.1126/science.1219424

ABSTRACT
Microbial communities can subsist at depth in marine sediments without fresh supply of organic matter for millions of years. At threshold sedimentation rates of 1 millimeter per 1000 years, the low rates of microbial community metabolism in the North Pacific Gyre allow sediments to remain oxygenated tens of meters below the sea floor. We found that the oxygen respiration rates dropped from 10 micromoles of O2 liter−1 year−1 near the sediment-water interface to 0.001 micromoles of O2 liter−1 year−1 at 30-meter depth within 86 million-year-old sediment. The cell-specific respiration rate decreased with depth but stabilized at around 10−3 femtomoles of O2 cell−1 day−1 10 meters below the seafloor. This result indicated that the community size is controlled by the rate of carbon oxidation and thereby by the low available energy flux.
 
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We have bacteria that do not seem to be bothered by radiation and some bacteria seem to use the heat from radioactive decay as a power source while being trapped a few 1000 meters under the ground for thousands to millions of years. The message seems to be that as long as there is energy, there is life.

But there are also fungi that actually seem to thrive on ionizing radiation by the use of the pigment melanin.

It is called a Radiotrophic fungus

http://www.scientificamerican.com/article.cfm?id=radiation-helps-fungi-grow

Do Fungi Feast on Radiation?

Apparently, but only if they contain melanin, the chemical that serves as skin pigment in humans

Like plants that grow toward the sun, dark fungi, blackened by the skin pigment melanin, gravitate toward radiation in contaminated soil. Scientists have observed the organisms—somewhere between plants and animals—blackening the land around the Chernobyl Nuclear Power Plant in Ukraine in the years since its 1986 meltdown. "Organisms that make melanin have a growth advantage in this soil," says microbiologist Arturo Casadevall of the Albert Einstein College of Medicine in New York City. "In many commercial nuclear reactors, the radioactive water becomes contaminated with melanotic organisms. Nobody really knows what the hell they are doing there."

Casadevall and his colleagues, however, have a theory. Based on experiments with three different types of fungi, they believe the melanin-containing breeds absorb the high levels of energy in ionizing radiation and somehow turn it into a biologically useful (and benign) form, akin to a dark and dangerous version of photosynthesis. "We were able to see significant growth of the black ones relative to the white ones in a radiation field," he says. "That is the observation. How you interpret it … is where the interesting speculations come in."

In a paper published online in PLoS One, Casadevall and his colleagues report that ionizing radiation changes the electron structure of the melanin molecule and that fungi with a natural melanin shell (the soil-dwelling Cladosporium sphaerospermum and yeastlike Wangiella dermatitidis varieties), which were deprived of other nutrients, grew better in the presence of radiation. They also report that fungi induced to produce a melanin shell (the human pathogen Cryptococcocus neoformans) grew well in such levels of radiation, unlike those sans pigment. Further, an albino mutant strain of W. dermatitidis failed to thrive as well as its black cousin when exposed to 500 times the normal amount of ionizing radiation (still well below the level of radiation necessary to kill tough fungal forms).

"The presumption has always been that we don't know why truffles and other fungi are black," Casadevall says. "If they have some primitive capacity to harvest sunlight or to harvest some kind of background radiation a lot of them would be using it."

Melanin drinks in ultraviolet rays, acting as a natural sunblock for human skin. "Melanin is very good at absorbing energy and then dissipating it as quickly as possible," says Jennifer Riesz, a biophysicist at the University of Queensland in Brisbane, Australia. "It does this by very efficiently changing the energy into heat."

But Casadevall and his colleague Ekaterina Dadachova, a nuclear chemist at Einstein, speculate that the melanin in this case acts like a step-down electric transformer, weakening the energy until it is useable by the fungi. "The energy becomes … low [at] a certain point where it can already be used by a fungus as chemical energy," Dadachova argues. "Protection doesn't play a role here. It is real energy conversion."

Mycologists and biophysicists find the notion both intriguing and potentially plausible. "Since melanin is used commonly by fungi—and other organisms—to protect themselves against UV radiation, it is perhaps not surprising that melanin would be affected by ionizing radiation,'' says Albert Torzilli, a mycologist at George Mason University in Virginia, adding that "the subsequent enhancement of growth, if true, is a novel response."

Riesz, for one, is skeptical. "It does not surprise me that fungi protected with higher levels of melanin might grow better when exposed to [ionizing radiation], since the nonprotected fungi are more likely to be harmed by the radiation," she says. "However, I find the claim that melanin is involved in energy capture and utilization to be unlikely."

More study is needed to confirm whether fungi will be able to add the ability to grow by harvesting radiation to their list of seeming superpowers, but it does raise the question of whether edible fungi—like mushrooms—have been harboring this function undiscovered for years. If true, melanin could be genetically engineered into photosynthetic plants to boost their productivity or melanin-bearing fungi could be used in clothing to shield workers from radiation or even farmed in space as astronaut food. The group plans further tests to see if fungi with melanin are converting other wavelengths of the electromagnetic spectrum into energy, as well.

"[Melanin] doesn't reflect any light; it's all going into it. Is it all disappearing into a black pigment and has no use whatsoever? Biology is incredibly inventive," Casadevall argues. After all, extremophile microbes thrive in the heat and acid of hydrothermal vents below the sea or live off the radiation of decaying radioactive rocks deep inside Earth's crust. "It's not that outlandish," Casadevall says, for fungi to harvest the energy in ionizing radiation with the help of melanin. But it is unexpected and strange.




http://en.wikipedia.org/wiki/Radiotrophic_fungus

Radiotrophic fungi are fungi which appear to use the pigment melanin to convert gamma radiation[1] into chemical energy for growth.[2] This proposed mechanism may be similar to anabolic pathways for the synthesis of reduced organic carbon (e.g., carbohydrates) in phototrophic organisms, which capture photons from visible light with pigments such as chlorophyll whose energy is then used in photolysis of water to generate usable chemical energy (as ATP) in photophosphorylation of photosynthesis. However, whether melanin-containing fungi employ a similar multi-step pathway as photosynthesis, or some chemosynthesis pathways, is unknown.

These were first discovered in 2007 as black molds growing inside and around the Chernobyl Nuclear Power Plant.[1] Research at the Albert Einstein College of Medicine showed that three melanin-containing fungi, Cladosporium sphaerospermum, Wangiella dermatitidis, and Cryptococcus neoformans, increased in biomass and accumulated acetate faster in an environment in which the radiation level was 500 times higher than in the normal environment. Exposure of C. neoformans cells to these radiation levels rapidly (within 20–40 minutes of exposure) altered the chemical properties of its melanin and increased melanin-mediated rates of electron transfer (measured as reduction of ferricyanide by NADH) 3 to 4-fold compared with unexposed cells.[2] Similar effects on melanin electron-transport capability were observed by the authors after exposure to non-ionizing radiation, suggesting that melanotic fungi might also be able to use light or heat radiation for growth.

However, melanization may come at some metabolic cost to the fungal cells: in the absence of radiation, some non-melanized fungi (that had been mutated in the melanin pathway) grew faster than their melanized counterparts. Limited uptake of nutrients due to the melanin molecules in the fungal cell wall or toxic intermediates formed in melanin biosynthesis have been suggested to contribute to this phenomenon.[2] It is consistent with the observation that despite being capable of producing melanin, many fungi do not synthesize melanin constitutively (i.e., all the time), but often only in response to external stimuli or at different stages of their development.[3] The exact biochemical processes in the suggested melanin-based synthesis of organic compounds or other metabolites for fungal growth, including the chemical intermediates (such as native electron donor and acceptor molecules) in the fungal cell and the location and chemical products of this process, are unknown.
Imagine that if there is enough of this fungi on the top soil and the radioactive source being under ground, the environment above the soil/ground would be not as radioactive as it seems...
 
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This is an interesting development : Research has been done explaining how epigenetics can play a role in developing rheumatoid arthritis by modifying dna after duplication by a process called DNA methylation. This might also give more insight in some auto immune diseases.

The big questions are of course, why does this DNA methylation occur and why on these specific sites on the dna strand after duplication ?


http://medicalxpress.com/news/2012-07-epigenetics-genes-rheumatoid-arthritis.html

It's not just our DNA that makes us susceptible to disease and influences its impact and outcome. Scientists are beginning to realize more and more that important changes in genes that are unrelated to changes in the DNA sequence itself – a field of study known as epigenetics – are equally influential.


A research team at the University of California, San Diego – led by Gary S. Firestein, professor in the Division of Rheumatology, Allergy and Immunology at UC San Diego School of Medicine – investigated a mechanism usually implicated in cancer and in fetal development, called DNA methylation, in the progression of rheumatoid arthritis (RA). They found that epigenetic changes due to methylation play a key role in altering genes that could potentially contribute to inflammation and joint damage. Their study is currently published in the online edition of the Annals of the Rheumatic Diseases.

"Genomics has rapidly advanced our understanding of susceptibility and severity of rheumatoid arthritis," said Firestein. "While many genetic associations have been described in this disease, we also know that if one identical twin develops RA that the other twin only has a 12 to 15 percent chance of also getting the disease. This suggests that other factors are at play – epigenetic influences."

DNA methylation is one example of epigenetic change, in which a strand of DNA is modified after it is duplicated by adding a methyl to any cytosine molecule (C) – one of the 4 main bases of DNA. This is one of the methods used to regulate gene expression, and is often abnormal in cancers and plays a role in organ development.

While DNA methylation of individual genes has been explored in autoimmune diseases, this study represents a genome-wide evaluation of the process in fibroblast-like synoviocytes (FLS), isolated from the site of the disease in RA. FLS are cells that interact with the immune cells in RA, an inflammatory disease in the joints that damages cartilage, bone and soft tissues of the joint.

In this study, scientists isolated and evaluated genomic DNA from 28 cell lines. They looked at DNA methylation patterns in RA FLS and compared them with FLS derived from normal individuals or patients with non-inflammatory joint disease. The data showed that the FLS in RA display a DNA methylome signature that distinguishes them from osteoarthritis and normal FLS. These FLS possess differentially methylated (DM) genes that are critical to cell trafficking, inflammation and cell–extracellular matrix interactions.

"We found that hypomethylation of individual genes was associated with increased gene expression and occurred in multiple pathways critical to inflammatory responses," said Firestein, adding that this led to their conclusion: Differentially methylated genes can alter FLS gene expression and contribute to the pathogenesis of RA.

Journal reference: Annals of the Rheumatic Diseases

Provided by University of California - San Diego



In this artist's rendering, a DNA molecule is methylated on both strands at the center cytosine. DNA methylation plays an important role in epigenetic gene regulation, and is involved in both normal development and in cancer. Credit: UC San Diego School of Medicine
 
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Some links with information about dna methylation :

http://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070
The Role of Methylation in Gene Expression
By: Theresa Phillips, Ph.D. (Write Science Right) © 2008 Nature Education
Citation: Phillips, T. (2008) The role of methylation in gene expression. Nature Education 1(1)


Not all genes are active at all times. DNA methylation is one of several epigenetic mechanisms that cells use to control gene expression.

There are many ways that gene expression is controlled in eukaryotes, but methylation of DNA (not to be confused with histone methylation) is a common epigenetic signaling tool that cells use to lock genes in the "off" position. In recent decades, researchers have learned a great deal about DNA methylation, including how it occurs and where it occurs, and they have also discovered that methylation is an important component in numerous cellular processes, including embryonic development, genomic imprinting, X-chromosome inactivation, and preservation of chromosome stability. Given the many processes in which methylation plays a part, it is perhaps not surprising that researchers have also linked errors in methylation to a variety of devastating consequences, including several human diseases.

5-azacytidine Experiments Provide Early Clues to the Role of Methylation in Gene Expression
Prior to 1980, there were a number of clues that suggested that methylation might play a role in the regulation of gene expression. For example, J. D. McGhee and G. D. Ginder compared the methylation status of the beta-globin locus in cells that did and did not express this gene. Using restriction enzymes that distinguished between methylated and unmethylated DNA, the duo showed that the beta-globin locus was essentially unmethylated in cells that expressed beta-globin but methylated in other cell types (McGhee & Ginder, 1979). This and other evidence of the time were indirect suggestions that methylation was somehow involved in gene expression.

Shortly after McGhee and Ginder published their results, a more direct experiment that examined the effects of inhibiting methylation on gene expression was performed using 5-azacytidine in mouse cells. 5-azacytidine is one of many chemical analogs for the nucleoside cytidine. When these analogs are integrated into growing DNA strands, some, including 5-azacytidine, severely inhibit the action of the DNA methyltransferase enzymes that normally methylate DNA. (Interestingly, other analogs, like Ara-C, do not negatively impact methylation.) Because most DNA methylation was known to occur on cytosine residues, scientists hypothesized that if they inhibited methylation by flooding cellular DNA with 5-azacytidine, then they could compare cells before and after treatment to see what impact the loss of methylation had on gene expression. Knowing that gene expression changes are responsible for cellular differentiation, these researchers used changes in cellular phenotypes as a proxy for gene expression changes (Table 1; Jones & Taylor, 1980).

Table 1: Effect of Cytidine Analogs on Cell Differentiation and DNA Methylation
Chemical Added Number of Differentiated Cells Amount of Methylation Measured
  • 3 μM cytidine (control) 0 100%
  • 0.3 μM Ara-C 0 127%
  • 3 μM 5-azacytidine 22,141 33%

This straightforward experiment demonstrated that it was not the removal of cytidine residues alone that resulted in changes in cell differentiation (because Ara-C did not have an impact on differentiation); rather, only those analogs that impacted methylation resulted in such changes. These experiments opened the door for investigators to better understand exactly how methylation impacts gene expression and cellular differentiation.

How and Where Are Genes Methylated?
Today, researchers know that DNA methylation occurs at the cytosine bases of eukaryotic DNA, which are converted to 5-methylcytosine by DNA methyltransferase (DNMT) enzymes. The altered cytosine residues are usually immediately adjacent to a guanine nucleotide, resulting in two methylated cytosine residues sitting diagonally to each other on opposing DNA strands. Different members of the DNMT family of enzymes act either as de novo DNMTs, putting the initial pattern of methyl groups in place on a DNA sequence, or as maintenance DNMTs, copying the methylation from an existing DNA strand to its new partner after replication. Methylation can be observed by staining cells with an immunofluorescently labeled antibody for 5-methylcytosine. In mammals, methylation is found sparsely but globally, distributed in definite CpG sequences throughout the entire genome, with the exception of CpG islands, or certain stretches (approximately 1 kilobase in length) where high CpG contents are found. The methylation of these sequences can lead to inappropriate gene silencing, such as the silencing of tumor suppressor genes in cancer cells.

Currently, the mechanism by which de novo DNMT enzymes are directed to the sites that they are meant to silence is not well understood. However, researchers have determined that some of these DNMTs are part of chromatin-remodeling complexes and serve to complete the remodeling process by performing on-the-spot DNA methylation to lock the closed shape of the chromatin in place.

The roles and targets of DNA methylation vary among the kingdoms of organisms. As previously noted, among Animalia, mammals tend to have fairly globally distributed CpG methylation patterns. On the other hand, invertebrate animals generally have a "mosaic" pattern of methylation, where regions of heavily methylated DNA are interspersed with nonmethylated regions. The global pattern of methylation in mammals makes it difficult to determine whether methylation is targeted to certain gene sequences or is a default state, but the CpG islands tend to be near transcription start sites, indicating that there is a recognition system in place.

Plantae are the most highly methylated eukaryotes, with up to 50% of their cytosine residues exhibiting methylation. Interestingly, in Fungi, only repetitive DNA sequences are methylated, and in some species, methylation is absent altogether, or it occurs on the DNA of transposable elements in the genome. The mechanism by which the transposons are recognized and methylated appears to involve small interfering RNA (siRNA). The whole silencing mechanism invoking DNMTs could be a way for these organisms to defend themselves against viral infections, which could generate transposon-like sequences. Such sequences can do less harm to the organism if they are prevented from being expressed, although replicating them can still be a burden (Suzuki & Bird, 2008). In other fungi, such as fission yeast, siRNA is involved in gene silencing, but the targets include structural sequences of the chromosomes, such as the centromeric DNA and the telomeric repeats at the chromosome ends.
The Role of Methylation in Gene Expression

For many years, methylation was believed to play a crucial role in repressing gene expression, perhaps by blocking the promoters at which activating transcription factors should bind. Presently, the exact role of methylation in gene expression is unknown, but it appears that proper DNA methylation is essential for cell differentiation and embryonic development. Moreover, in some cases, methylation has observed to play a role in mediating gene expression. Evidence of this has been found in studies that show that methylation near gene promoters varies considerably depending on cell type, with more methylation of promoters correlating with low or no transcription (Suzuki & Bird, 2008). Also, while overall methylation levels and completeness of methylation of particular promoters are similar in individual humans, there are significant differences in overall and specific methylation levels between different tissue types and between normal cells and cancer cells from the same tissue.

Researchers have also determined that mice that lack a particular DNMT have reduced methylation levels and die early in development (Suzuki & Bird, 2008). This is not the case for all eukaryotes, however; some organisms, such as the yeast Saccharomyces cerevisiae and the nematode worm Caenorhabditis elegans, are thought to have no methylated DNA at all (although, at least in yeast, there are sequences in their genomes that are homologous to those that code for the DNMT enzymes).

DNA Methylation and Histones

Although patterns of DNA methylation appear to be relatively stable in somatic cells, patterns of histone methylation can change rapidly during the course of the cell cycle. Despite this difference, several studies have indicated that DNA methylation and histone methylation at certain positions are connected. For instance, results of immunoprecipitation studies using human cells suggest that DNA methylation and histone methylation work together during replication to ensure that specific methylation patterns are passed on to progeny cells (Sarraf & Stancheva, 2004). Indeed, evidence has been presented that in some organisms, such as Neurospora crassa (Tamaru & Selker, 2001) and Arabidopsis thaliana (Jackson et al., 2002), H3-K9 methylation (methylation of a specific lysine residue in the histone H3) is required in order for DNA methylation to take place. However, exceptions have been observed in which the relationship is reversed. In one study, for example, H3 methylation was reduced at a tumor suppressor gene in cells deficient in DNA methyltransferase (Martin & Zhang, 2005).

In an interestingly coordinated process, proteins that bind to methylated DNA also form complexes with the proteins involved in deacetylation of histones. Therefore, when DNA is methylated, nearby histones are deacetylated, resulting in compounded inhibitory effects on transcription. Likewise, demethylated DNA does not attract deacetylating enzymes to the histones, allowing them to remain acetylated and more mobile, thus promoting transcription.

In most cases, methylation of DNA is a fairly long-term, stable conversion, but in some cases, such as in germ cells, when silencing of imprinted genes must be reversed, demethylation can take place to allow for "epigenetic reprogramming." The exact mechanisms for demethylation are not entirely understood; however, it appears that this process may be mediated by the removal of amino groups by DNA deaminases (Morgan et al., 2004). After deamination, the DNA has a mismatch and is repaired, causing it to become demethylated. In fact, studies using inhibitors of one DNMT enzyme showed that this enzyme was involved in not only DNA methylation, but also in the removal of amino groups.
DNA Methylation and Disease

Given the critical role of DNA methylation in gene expression and cell differentiation, it seems obvious that errors in methylation could give rise to a number of devastating consequences, including various diseases. Indeed, medical scientists are currently studying the connections between methylation abnormalities and diseases such as cancer, lupus, muscular dystrophy, and a range of birth defects that appear to be caused by defective imprinting mechanisms (Robertson, 2005). The results of these studies will be invaluable for treating these disorders, as well as for understanding and preventing complications that can arise during embryonic development due to abnormalities in X-chromosome methylation and gene imprinting.


To date, a large amount of research on DNA methylation and disease has focused on cancer and tumor suppressor genes. Tumor suppressor genes are often silenced in cancer cells due to hypermethylation. In contrast, the genomes of cancer cells have been shown to be hypomethylated overall when compared to normal cells, with the exception of hypermethylation events at genes involved in cell cycle regulation, tumor cell invasion, DNA repair, and others events in which silencing propagates metastasis (Figure 1; Robertson, 2005). In fact, in certain cancers, such as that of the colon, hypermethylation is detectable early and might serve as a biomarker for the disease.


Figure 1: DNA methylation and cancer.
This diagram shows a representative region of genomic DNA in a normal cell. The region contains repeat-rich, hypermethylated pericentromeric heterochromatin and an actively transcribed tumor suppressor gene (TSG) associated with a hypomethylated CpG island (indicated in red). In tumor cells, repeat-rich heterochromatin becomes hypomethylated, and this contributes to genomic instability (a hallmark of tumor cells) through increased mitotic recombination events. De novo methylation of CpG islands also occurs in cancer cells, and it can result in the transcriptional silencing of growth-regulatory genes. These changes in methylation are early events in tumorigenesis. (Reproduced from Robertson, 2005.)
Copyright 2005 Nature Publishing Group, Robertson, K., DNA methylation and human disease, Nature Reviews Genetics 6, 597-561
Summary


Within the past thirty years, researchers have discovered numerous details about the process of DNA methylation. For instance, scientists now know that methylation plays a critical role in the regulation of gene expression, and they have also determined that this process tends to occur at certain locations within the genomes of different species. Furthermore, DNA methylation has been shown to play a vital role in numerous cellular processes, and abnormal patterns of methylation have been liked to several human diseases. Nonetheless, as with other topics in the field of epigenetics, gaps remain in our knowledge of DNA methylation. As new laboratory techniques are developed and additional genomes are mapped, scientists will no doubt continue to uncover many of the unknowns of how, when, and where DNA is methylated, and for what purposes.

References and Recommended Reading

Jackson, J., et al. Control of CpNpG DNA methylation by the kryptonite histone H3 methyltransferase. Nature 416, 556–560 (2002) doi:10.1038/nature731 (link to article)

Jones, P. A., & Taylor, S. M. Cellular differentiation, cytidine analogs, and DNA methylation. Cell 20, 85–93 (1980)

Martin, C., & Zhang, Y. The diverse functions of histone lysine methylation. Nature Reviews Molecular Cell Biology 6, 838–849 (2005) doi:10.1038/nrm1761 (link to article)

McGhee, J. D., & Ginder, G. D. Specific DNA methylation sites in the vicinity of the chicken beta-globin genes. Nature 280, 419–420 (1979) (link to article)

Morgan, H., et al. Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues. Journal of Biological Chemistry 279, 52353–52360 (2004) doi:10.1074/jbc.M407695200

Robertson, K. DNA methylation and human disease. Nature Reviews Genetics 6, 597–610 (2005) doi:10.1038/nrg1655 (link to article)
Sarraf, S., & Stancheva, I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Molecular Cell 15, 595–605 (2004) doi:10.1016/j.molcel.2004.06.043

Suzuki, M., & Bird, A. DNA methylation landscapes: Provocative insights from epigenomics. Nature Reviews Genetics 9, 465–476 (2008) doi:10.1038/nrg2341 (link to article)

Tamaru, H., & Selker, E. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001) doi:10.1038/35104508 (link to article)

http://en.wikipedia.org/wiki/DNA_methylation
DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring (cytosine and adenine are two of the four bases of DNA). This modification can be inherited through cell division.

DNA methylation is a crucial part of normal organismal development and cellular differentiation in higher organisms. DNA methylation stably alters the gene expression pattern in cells such that cells can "remember where they have been" or decrease gene expression; for example, cells programmed to be pancreatic islets during embryonic development remain pancreatic islets throughout the life of the organism without continuing signals telling them that they need to remain islets. DNA methylation is typically removed during zygote formation and re-established through successive cell divisions during development. However, the latest research shows that hydroxylation of methyl groups occurs rather than complete removal of methyl groups in zygote.[1] Some methylation modifications that regulate gene expression are inheritable and are referred to as epigenetic regulation.

In addition, DNA methylation suppresses the expression of viral genes and other deleterious elements that have been incorporated into the genome of the host over time. DNA methylation also forms the basis of chromatin structure, which enables cells to form the myriad characteristics necessary for multicellular life from a single immutable sequence of DNA. DNA methylation also plays a crucial role in the development of nearly all types of cancer.[2]



Genomic imprinting :
http://en.wikipedia.org/wiki/Genomic_imprinting

Genomic imprinting is a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. It is an inheritance process independent of the classical Mendelian inheritance. Imprinted alleles are silenced such that the genes are either expressed only from the non-imprinted allele inherited from the mother (e.g. H19 or CDKN1C), or in other instances from the non-imprinted allele inherited from the father (e.g. IGF-2). Forms of genomic imprinting have been demonstrated in insects, mammals and flowering plants.

Genomic imprinting is an epigenetic process that involves methylation and histone modifications in order to achieve monoallelic gene expression without altering the genetic sequence. These epigenetic marks are established in the germline and are maintained throughout all somatic cells of an organism.

Appropriate expression of imprinted genes is important for normal development, with numerous genetic diseases associated with imprinting defects including Beckwith–Wiedemann syndrome, Silver–Russell syndrome, Angelman syndrome and Prader–Willi syndrome.
 
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Time to start with fungi, and the role these fungi play in life on Earth.
Soil fungi are potent carbon catchers. Soil Fungi draw in a lot of carbon and bind it into the soil. Details i do not have yet about how it works but will come...

www.nicholls.edu/biol-ds/Biol156/Lectures/Fungi.pdf

Some fungi (also called molds) contain mycotoxins that are suspected to be the real cause of so called diagnosed auto immune diseases in some cases.
mycotoxins can create a myriad of symptoms ranging from neural disorders to playing a role in developing cancer.


A pdf that might give some information :
www.cancerfungus.com/pdf/fungi-nexus.pdf
 
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This is surely interesting : Opioid drugs such as heroin and morphine, bind to the TLR4 receptor.
I had to look it up to understand it :
TLR4 detects lipopolysaccharides. Lipopolysaccharides acts as an endotoxin and are found on the outer membrane of gram negative bacteria.
When these bacteria are detected by the innate immune system, the immune system found in the digestive system and IIRC all orifices.
The first amazing thing is that the TLR4 receptor seems to amplify the addictive effects of opioid drugs. I never knew that these drugs can also influence the immune system, contributing to the addictive effects.
The second amazing thing is that these great researchers seem to have found a way to stop the addictive effects and to remove the painful withdrawal effects when stopping heroin and morphine usage.



http://medicalxpress.com/news/2012-08-scientists-block-heroin-morphine-addiction.html

In a major breakthrough, an international team of scientists has proven that addiction to morphine and heroin can be blocked, while at the same time increasing pain relief.

The team from the University of Adelaide and University of Colorado has discovered the key mechanism in the body's immune system that amplifies addiction to opioid drugs.
Laboratory studies have shown that the drug (+)-naloxone (pronounced: PLUS nal-OX-own) will selectively block the immune-addiction response.
The results – which could eventually lead to new co-formulated drugs that assist patients with severe pain, as well as helping heroin users to kick the habit – will be published tomorrow in the Journal of Neuroscience.
"Our studies have shown conclusively that we can block addiction via the immune system of the brain, without targeting the brain's wiring," says the lead author of the study, Dr Mark Hutchinson, ARC Research Fellow in the University of Adelaide's School of Medical Sciences.
"Both the central nervous system and the immune system play important roles in creating addiction, but our studies have shown we only need to block the immune response in the brain to prevent cravings for opioid drugs."
The team has focused its research efforts on the immune receptor known as Toll-Like receptor 4 (TLR4).
"Opioid drugs such as morphine and heroin bind to TLR4 in a similar way to the normal immune response to bacteria. The problem is that TLR4 then acts as an amplifier for addiction," Dr Hutchinson says.
"The drug (+)-naloxone automatically shuts down the addiction. It shuts down the need to take opioids, it cuts out behaviours associated with addiction, and the neurochemistry in the brain changes – dopamine, which is the chemical important for providing that sense of 'reward' from the drug, is no longer produced."

Senior author Professor Linda Watkins, from the Center for Neuroscience at the University of Colorado Boulder, says: "This work fundamentally changes what we understand about opioids, reward and addiction. We've suspected for some years that TLR4 may be the key to blocking opioid addiction, but now we have the proof.

"The drug that we've used to block addiction, (+)-naloxone, is a non-opioid mirror image drug that was created by Dr Kenner Rice in the 1970s. We believe this will prove extremely useful as a co-formulated drug with morphine, so that patients who require relief for severe pain will not become addicted but still receive pain relief . This has the potential to lead to major advances in patient and palliative care," Professor Watkins says.

The researchers say clinical trials may be possible within the next 18 months.

Journal reference: Journal of Neuroscience

Provided by University of Adelaide

More background information :
http://en.wikipedia.org/wiki/TLR_4
http://en.wikipedia.org/wiki/Innate_immune_system
http://en.wikipedia.org/wiki/Lipopolysaccharide
http://en.wikipedia.org/wiki/Gram-negative
 
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The hazardous effects of consuming way to much sugar are explained in detail here. Humans are hardwired to like sugar. It is an inherited evolutionary trait from the food we consume.

Here is the 60 minutes short version :
It explains about new research where it is found that the blood chemistry even of young people changes drastically when consuming large amounts of sugar. How the liver reacts to to much fructose.
http://www.cbsnews.com/video/watch/?id=7417238n&tag=contentMain;contentBody

And here is the long version with all the details from Robert H. Lustig :
http://www.youtube.com/watch?v=dBnniua6-oM

A documentary about addiction :
http://www.cbsnews.com/video/watch/?id=7406968n&tag=contentMain;contentBody
When consuming drugs and especially in large amounts.
It shows that one does not only get conditioned like a dog of Pavlov, but also the brain damage that one can experience, weakens the will. Thus it becomes more difficult to just say no. An addict is attacked from multiple angles. The reward system and the pleasure system reacting and the basis of self control in the prefrontal cortex becomes weakened.

Interesting side note :
The researcher is Dr Nora Volkow. She is the great granddaughter of Leon Trotsky.



Here is an idea i have for people with addictions :
Think about how humans start salivating when sniffing fresh sweet fruit...
If you do not believe me, try it out yourself.
If you have some addiction problem and you want to get rid of it...
Start living on a low sugar diet. When you crave for, for example a cigarette or a joint just eat some fresh sweet fruit. It will help you get your control back. Because sugar is also stimulating the so called "reward center and the pleasure center." Then stop consuming sugar and go back to the low sugar diet. Every time you crave, give in by consuming some sweet fruit.
Maybe it will also work for hard drugs like cocaine and to get of addictive medicines that have similar effects as cocaine.
 
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Sometimes life is not easy being an insect. Those pesky humans spray insecticides on all those tasty vegetables from which an insect gets sick and dies.

But one insect species has acquired a novel way to become fully impervious for a certain type of insecticide commonly used. At some crossing of events (some moment in time if you please), the Riptortus pedestris ingested a certain bacteria. And that bacteria called Burkholderia consumes the insecticide fenitrothion rendering it (i guess amounts) harmless enough for the insect called the "bean bug".

http://phys.org/news/2012-04-bean-bugs-harbor-bacteria-safe.html#nRlv

Phys.org) -- Conventional wisdom says that in order for a species of insect to develop resistance to an antibiotic, several generations have to pass, whereby genes from those that have some natural resistance pass them on to their offspring. But sometimes conventional wisdom fails to take into account how some bugs can find a work around. In this case, it’s the bean bug. Researchers in Japan have found that for Riptortus pedestris, the common bean bug, there is a much quicker path. All they have to do is ingest the Burkholderia bacteria. Doing so, the team says in their paper published in the Proceedings of the National Academy of Sciences, makes them nearly impervious to the insecticide fenitrothion, which has historically been used to treat soy bean plants to protect them from the bugs that dine on them.

To find out what was going on with bean bugs and the Burkholderia bacteria, the researchers added the bacteria to potting soil in the lab, where they flourished. They followed that by adding fenitrothion, which the bugs ate with abandon. Next, they introduced some young bean bugs (nymphs) into the pot which ate soy bean seedlings the researchers added to the mix.
In examining the guts of the bugs, the researchers found the bacteria continued to thrive and the bugs became immune to the effects of the insecticide as a result because the bacteria was eating it before it could harm them. Normally, they say, up to eighty percent of bean bugs will die from such an exposure.
In further tests, the researchers found that bean bugs can harbor up to a hundred million bacteria in their guts, which tends to make them larger than others of the same species.
Fortunately for farmers in Japan, however, it doesn’t appear that many of the bean bugs, or their close cousin chinch bugs, swallow much of the bacteria in the wild though. Tests done found that only eight percent of such bugs had Burkholderia bacteria in their guts in one area, and none in another, thus very few were able to develop an immunity to fenitrothion.
The research team says that this symbiotic relationship between bean bugs and Burkholderia bacteria, providing the bugs with immunity from an insecticide, is the first such example ever found. But they also note that because it’s been found in this case, it’s likely occurring in other relationships as well.

More information: Symbiont-mediated insecticide resistance, PNAS, Published online before print April 23, 2012, doi: 10.1073/pnas.1200231109

Abstract
Development of insecticide resistance has been a serious concern worldwide, whose mechanisms have been attributed to evolutionary changes in pest insect genomes such as alteration of drug target sites, up-regulation of degrading enzymes, and enhancement of drug excretion. Here, we report a previously unknown mechanism of insecticide resistance: Infection with an insecticide-degrading bacterial symbiont immediately establishes insecticide resistance in pest insects. The bean bug Riptortus pedestris and allied stinkbugs harbor mutualistic gut symbiotic bacteria of the genus Burkholderia, which are acquired by nymphal insects from environmental soil every generation. In agricultural fields, fenitrothion-degrading Burkolderia strains are present at very low densities. We demonstrated that the fenitrothion-degrading Burkholderia strains establish a specific and beneficial symbiosis with the stinkbugs and confer a resistance of the host insects against fenitrothion. Experimental applications of fenitrothion to field soils drastically enriched fenitrothion-degrading bacteria from undetectable levels to >80% of total culturable bacterial counts in the field soils, and >90% of stinkbugs reared with the enriched soil established symbiosis with fenitrothion-degrading Burkholderia. In a Japanese island where fenitrothion has been constantly applied to sugarcane fields, we identified a stinkbug population wherein the insects live on sugarcane and ≈8% of them host fenitrothion-degrading Burkholderia. Our finding suggests the possibility that the symbiont-mediated insecticide resistance may develop even in the absence of pest insects, quickly establish within a single insect generation, and potentially move around horizontally between different pest insects and other organisms.

Journal reference: Proceedings of the National Academy of Sciences

http://en.wikipedia.org/wiki/Burkholderia_pseudomallei



 
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Perhaps the bacteria Burkholderia pseudomallei infected the plants that the bean bugs eat. It seems that this bacteria that lives in soil and water is capable of infecting plants as well. Since bacteria can swap genes (plasmids) easily, this might be a trend. The bacteria might as well cause some disease in the bean bug as well but not problematic enough to be a real issue. Instant death or having a shorter lifespan. Evolutionary wise, even a not ideal symbiotic relationship can in such a specific case be very beneficial for the survival of a species.

This article is how Burkholderia pseudomallei infects tomato plants.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823722/?tool=pmcentrez

An excerpt :
Background
Burkholderia pseudomallei is the causative agent for melioidosis, a disease with significant mortality and morbidity in endemic regions. Its versatility as a pathogen is reflected in its relatively huge 7.24 Mb genome and the presence of many virulence factors including three Type Three Secretion Systems known as T3SS1, T3SS2 and T3SS3. Besides being a human pathogen, it is able to infect and cause disease in many different animals and alternative hosts such as C. elegans.

Results
Its host range is further extended to include plants as we demonstrated the ability of B. pseudomallei and the closely related species B. thailandensis to infect susceptible tomato but not rice plants. Bacteria were found to multiply intercellularly and were found in the xylem vessels of the vascular bundle. Disease is substantially attenuated upon infection with bacterial mutants deficient in T3SS1 or T3SS2 and slightly attenuated upon infection with the T3SS3 mutant. This shows the importance of both T3SS1 and T3SS2 in bacterial pathogenesis in susceptible plants.

Conclusions
The potential of B. pseudomallei as a plant pathogen raises new possibilities of exploiting plant as an alternative host for novel anti-infectives or virulence factor discovery. It also raises issues of biosecurity due to its classification as a potential bioterrorism agent.


Background
Burkholderia pseudomallei is a Gram-negative bacterium that is the causative agent for melioidosis, a disease endemic in Southeast Asia and Northern Australia with significant morbidity and mortality [1,2]. The bacterium exhibits broad host range and has been shown to cause disease in cattle, pigs, goats, horses, dolphins, koalas, kangaroos, deers, cats, dogs and gorillas [3]. Acquisition of the bacterium could be through inhalation of aerosol, ingestion of contaminated water and inoculation through open skin [4]. In humans, the disease could present with varied manifestations ranging from asymptomatic infection, localized disease such as pneumonia or organ abscesses to systemic disease with septicemia [5]. The disease could be acute or chronic, and relapse from latency is possible [6].

The versatility of B. pseudomallei as a pathogen is reflected in its huge 7.24 Mb genome organized into two chromosomes [7]. One of the most important virulence factors that has been partially characterized in B. pseudomallei is its Type Three Secretion Systems (T3SS), of which it has three [8,9]. Each T3SS typically consists of a cluster of about 20 genes encoding structural components, chaperones and effectors which assemble into an apparatus resembling a molecular syringe that is inserted into host cell membrane for the delivery of bacterial effectors into host cell cytosol. One of the B. pseudomallei T3SS known as Bsa or T3SS3 resembles the inv/mxi/spa T3SS of Salmonella and Shigella, and has been shown to be important for disease in animal models [10]. The other two T3SS (T3SS1 and 2) resemble the T3SS of plant pathogen Ralstonia solanacearum [11] and do not contribute to virulence in mammalian models of infection [12]. Being a soil saprophyte and having the plant pathogen-like T3SS raise the possibility that B. pseudomallei could also be a plant pathogen. As B. pseudomallei is a risk group 3 agent with specific requirements for containment, we first test this hypothesis using the closely related species B. thailandensis as a surrogate model especially in experiments where risk of aerosolization is high, before we verify key experiments with B. pseudomallei. B. thailandensis is considered largely avirulent in mammalian hosts unless given in very high doses [13,14]. We infected both tomato as well as rice plants with B. pseudomallei to determine their susceptibility to disease. Furthermore, the role of the three B. pseudomallei T3SS in causing plant disease is evaluated and the implication of the ability of B. pseudomallei to infect plants is discussed.


Methods
Bacterial strains, plasmids and growth conditions
All bacterial strains, plasmids used and constructed are listed in Table ​Table1.1. All strains of B. thailandensis
and B. pseudomallei were cultured at 37°C in Luria-Bertani (LB) medium or on Tryptone Soy Agar (TSA) plates. To obtain log-phase culture, 250 μL of overnight culture was inoculated into 5 mL LB medium and cultured for 2.5 hours with constant shaking at 100 rpm. Escherichia coli strains were cultivated at 37°C in LB medium. Antibiotics were added to the media at the following final concentrations of 100 μg/mL (ampillicin); 25 μg/mL (kanamycin); 10 μg/mL (tetracycline); and 25 μg/mL (zeocin) for E. coli, 250 μg/mL (kanamycin); 40 μg/mL (tetracycline); 25 μg/mL (gentamicin) and 1000 μg/mL (zeocin) for B. pseudomallei. All antibiotics were purchased from Sigma (St Louis, MO, USA).

Plant material
Tomato seeds of the Solanum lycopersicum variety Season Red F1 Hybrid (Known-You Seeds Distribution (S.E.A) Pte Ltd) and Arabidopsis thaliana (Loh Chiang Shiong, NUS) were surface sterilized with 15% bleach solution for 15 minutes with vigorous shaking. The seeds were rinsed in sterile distilled water and germinated in MS agar medium. The seedlings were cultivated with a photoperiod of 16 hour daylight and 8 hour darkness. One month old plantlets were used for infection. Tomato plantlets were transferred into 50 mL Falcon tubes with 5 mL of liquid MS medium for infection while 1 mL of MS medium was used for Arabidopsis. Rice seeds (Japonica nipponbare) were obtained from Dr Yin Zhong Zhao (Temasek Life Sciences Laboratories, Singapore). Seeds were surface sterilized as described above. The seeds were rinsed in sterile distilled water and germinated in N6 agar medium. The germinated seedlings were placed on N6 agar supplemented with 2 mg/mL of 2, 4-dichlorophenyoxyacetic acid (2, 4-D) in the dark to induce callus production. The callus were regenerated on N6 medium supplemented with 2 mg/mL Benzylaminopurine (BA), 1 mg/mL Naphthylacetic Acid (NAA), 1 mg/mL Indole-3-acetic acid (IAA) and 1 mg/mL Kinetin under 16 hour daylight and 8 hour dark photoperiod. Rice plantlets were transferred and maintained in MS agar medium. The plantlets were transferred into 50 mL Falcon tubes with 5 mL of liquid MS medium for infection. Some plantlets were also wounded by cutting off the roots before being transferred.

Plant infection
Tomato, rice and Arabidopsis plantlets were infected with log phase cultures at the concentration of 1 × 107 colony forming units (cfu)/5 mL medium by immersing only the roots of the plantlets in the inoculum in a 50 mL tube. The plantlets were maintained at 24-25°C, shaking at 100 rpm. The plantlets were observed for symptoms such as yellowing of leaves, blackening of the leaf veins, wilting and necrosis daily over 7 days. Each plantlet was scored daily on a disease index score of 1 to 5 based on how extensive the symptoms were as calculated by the percentage of the plant with symptoms (1: no symptoms; 2: 1 to 25% of the plant showed symptoms; 3: 26 to 50% of the plant showed symptoms; 4: 51 to 75% of the plant showed symptoms; 5: 76 to 100% of the plant showed symptoms or the plant was dead) [15]. Each experiment included at least 12 to 20 plantlets infected with bacteria except for experiments with rice and Arabidopsis plantlets where 6 plantlets were used. All experiments were repeated at least twice.
Multiplication of B. thailandensis in tomato plantlets and leaves

Tomato plantlets were infected with bacteria through unwounded roots and three leaves from each plantlet were excised at day 1, 3, 5 and 7 after infection. The leaves were macerated in 1 mL PBS with a micro-pestle, serially diluted and plated on TSA plates in duplicates. Tomato leaves were infected by cutting with a pair of scissors dipped in 1 × 109 cfu/mL of B. thailandensis. Five plantlets were used in each experiment. At days 1 and 3 after infection, one infected leaf from each plantlet was excised, washed with 10% bleach solution for 1 min and rinsed with sterile water. The leaf was blotted dry on sterile filter paper and imprinted on TSA agar plates to determine if there were any bacteria on the surface of the leaves. The imprinted plates were incubated at 37°C for 24 hours before checking for any bacteria growth. The leaves were then weighed and macerated in 1 mL PBS with a micro-pestle, serially diluted and plated on TSA plates in duplicates. Only leaf samples which did not show any bacteria growth on the imprinted plates will be counted to avoid counting contaminating bacteria from leaf surfaces.

Transmission Electron Microscope (TEM)
Tomato leaf and rice blade were infected by cutting with a pair of scissors dipped in 1 × 109 cfu/mL of B. pseudomallei strain KHW or B. thailandensis. One day after infection, the infected tomato leaf and rice blade were excised for TEM. One millimeter from the infected leaf/blade edge were cut and discarded to avoid contamination from extracellular bacteria at the infection site. A further two millimeter from the infected leaf/blade edge were then cut and sliced into smaller sections and fixed with 4% glutaraldehyde in 0.1 M phosphate buffer under vacuum for 4 hours. It was post-fixed with 1% osmium tetroxide in 0.1 M phosphate buffer for 1 hour at 4°C. Samples were dehydrated sequentially through 30%, 50%, 70%, 90%, 100% ethanol, and finally in propylene oxide prior to infiltration with Spurr resin [16]. Samples were embedded in 100% spur resin and polymerized at 70°C overnight. Ultra-thin sections were cut on a Leica Ultracut UCT ultra-microtome and examined with a transmission electron microscope (JEM1230, JEOL, Japan) at 120 kV.
Growth of bacteria in different media

Overnight cultures were used to inoculate 5 mL of LB and Murashige and Skoog (MS) [17] medium to a starting optical density at 600 nm of 0.1. The cultures were incubated at 37°C for LB medium and 25°C for MS medium. Optical density at 600 nm for all cultures was measured at 0, 2.5, 6 and 24 hours. All experiments were repeated twice with duplicates.
Generation of B. pseudomallei T3SS1, T3SS2 and T3SS3 mutants

Approximate one kb fragments upstream and downstream of the T3SS1, T3SS2 or T3SS3 locus were amplified from B. pseudomallei KHW genomic DNA and subsequently cloned into pK18mobsacB. The tet cassette from pGEM-tet or zeo cassette (kindly provided by Dr Herbert Schweizer, Colorado State University, USA) from pCLOXZ1 was inserted between the upstream and downstream fragments resulting in pT3SS1/upstream/downstream/tet, pT3SS2/upstream/downstream/tet, and pT3SS3/upstream/downstream/zeo. The plasmids were electroporated into SM10 conjugation host and conjugated into B. pseudomallei strain KHW. Homologous recombination was selected for retention of antibiotic marker (Tet or Zeo) linked to the mutation and loss of the plasmid marker (Km) to generate KHWΔT3SS1, KHWΔT3SS2 and KHWΔT3SS3. Each mutant was confirmed by PCR for the loss of a few representative T3SS genes in the locus.
Cytotoxicity assay on THP-1 cells

Human monocytic cell line THP-1 were maintained in RPMI 1640 (Sigma), supplemented with 10% Fetal Calf Serum (FCS, Hyclone Laboratories, Logan, UT), 200 mM L-glutamine, 100 Unit/mL penicillin and 100 μg/mL streptomycin. THP-1 cells were seeded at a concentration of 1 × 106 cells per 100 μL in 96-well plate in medium without FCS and antibiotics. Log phase bacteria were used for infection at multiplicity of infection (MOI) of 100:1. Kanamycin (250 μg/mL) was added one hour after infection to suppress the growth of extracellular bacteria. Supernatant was collected 6 hours after infection. Lactate dehydrogenase (LDH) activity in the supernatant was measured with the Cytotoxicity Detection Kit (Roche) according to manufacturer's instruction. Percentage cytotoxicity was calculated by the formula:

Statistical analysis
Average disease scores with standard deviation were calculated based on at least 100 tomato plantlets infected with each strain of bacteria or mutant. Data were analyzed using repeated measure analysis of variance [18]. All statistical analyses were performed using SPSS version 17 software (SPSS Inc). A p value of less than 0.001 is considered significant.

Using B. thailandensis infection of tomato plantlets as a model
To mimic infection via a possible natural route, the unwounded roots of tomato plantlets were immersed in media inoculated with 1 × 107 cfu of bacteria. Only the roots were in contact with the inoculum. Tomato plantlets infected via the roots by B. thailandensis showed progressive symptoms such as yellowing of leaves, blackening of the leaf veins, wilting and necrosis whereas uninfected plantlets remained healthy and did not show any disease symptoms throughout the period (Fig 1A-B). Most
infected plantlets were dead on day 7. All plantlets were monitored over a period of seven days. Disease was scored daily for every plantlet on an index from 1-5 based on the extent of symptoms presented as described in Methods. The average disease score for a particular day represent the mean disease scores for all the plantlets with the same treatment on that day. As infection progressed over time, the average disease score for B. thailandensis-infected plants increased progressively, reaching a maximum disease score of 5 on day 7 (Fig ​(Fig1C).1C). In contrast, plantlets infected with E. coli in the same manner via the roots showed a slight progression of average disease scores over time and reached a maximum disease score of 2 on day 7 (Fig ​(Fig1C),1C), demonstrating that the extensive disease and death seen was specific to B. thailandensis infection and not due to non-specific stress induced by the experimental manipulations.

For a phytopathogen to successfully colonize the plant, it must be able to replicate intercellularly [19]. To determine whether bacteria are able to replicate intercellularly, we sampled leaves from two representative plantlets which had been inoculated with bacteria via unwounded roots at 1, 3, 5 and 7 days post-inoculation. Three leaves were sampled at each time-point per plantlet. Both plantlets showed a progressive increase in bacterial load in their leaves over time (Fig ​(Fig1D1D).
Susceptibility of tomato plantlets to B. pseudomallei infection

Having established that B. thailandensis can infect tomato plantlets and cause disease, we determine whether B. pseudomallei would similarly infect tomato plantlets. We included strains isolated from humans, animals or the environment such as two clinical isolates (K96243 and KHW), a kangaroo isolate 561, two bird isolates (612 and 490) and two soil isolates (77/96 and 109/96) on their ability to infect tomato plants. B. pseudomallei is able to infect tomato plantlets to a similar degree as B. thailandensis with almost identical disease symptoms. All isolates were able to infect and cause disease to a similar extent (Fig ​(Fig2),2), showing that the ability to infect susceptible plants is unlikely to be strain-specific.

Localization of bacteria at site of infection
Having established the ability of both B. thailandensis and B. pseudomallei to be phytopathogens capable of infecting tomato plants, we next examined the localization of the bacteria upon inoculation into the leaf via TEM. We first examined whether bacteria inoculated into the leaves were able to survive and replicate. To ensure that there were no bacteria on the leaf surfaces, the leaves were surface sterilized with bleach and washed in sterile water before weighing and maceration. B. thailandensis was able to replicate in the leaves after inoculation (Fig ​(Fig3A).3A). The number of bacteria increased by about 10 fold
three days after infection although the numbers did not reach statistical significance by the student t test (p > 0.05). When examined under TEM, B. pseudomallei and B. thailandensis could be found in the xylem of the vascular bundle of the inoculated leaf (Fig 3B-C). The rest of the surrounding cells were not
colonized, suggesting that the bacteria spread to the rest of plant through the xylem vessels.

The role of T3SS in plant infection
To determine the role of T3SS in plant infection, we created B. pseudomallei deletion mutants lacking the entire region of T3SS1, T3SS2 or T3SS3 in strain KHW (Table ​(Table1).1). We first examined these mutants in
the established macrophage cytotoxicity model and confirmed the necessity of T3SS3 in mediating cytotoxicity [20] whereas mutants losing T3SS1 and T3SS2 were as cytotoxic as wildtype bacteria to THP-1 cells (Fig ​(Fig4A).4A). This shows that T3SS1 and T3SS2 are not involved in mediating cytoxicity to
mammalian cells. To exclude the possibility that any defect we see with the T3SS mutants would be due to a reduced fitness, we ascertained that all mutants grew as well as wildtype bacteria in LB and plant MS medium (Fig 4B-C). However, infection of tomato plantlets via unwounded roots showed that plants
infected by the T3SS1 and T3SS2 mutants exhibited significant delay in disease compared to plants infected by wildtype bacteria (Fig ​(Fig4D).4D). Statistical analysis of the average disease score over 7 days
showed that the T3SS1, 2 and 3 mutants were significantly less virulent from the wildtype bacteria (p < 0.001). T3SS1 and T3SS2 mutants were also significantly less virulent compared to the T3SS3 mutant (p < 0.001). This shows that both T3SS1 and T3SS2 contribute significantly to pathogen virulence towards tomato plants. The T3SS3 mutant also showed an intermediate degree of virulence between wildtype bacteria and the T3SS1 and T3SS2 mutants, likely because T3SS3 has a non-redundant role in mediating virulence in the susceptible tomato plants.

Susceptibility of rice and Arabidopsis plantlets to B. pseudomallei and B. thailandensis infection
Both B. thailandensis and B. pseudomallei did not cause any discernible symptoms in rice plantlets when infected via roots (unwounded or wounded) nor via inoculation through the leaves. B. thailandensis and B. pseudomallei infection of rice plantlets showed identical disease scores over 7 days (Fig &#8203;(Fig5A).5A). We
were unable to recover any bacteria from the leaves after infection via the roots. When bacteria were inoculated directly into the leaf blade, no bacteria were recoverable from the leaf one day after inoculation, indicating a lack of establishment of infection. The inoculated leaves did not show any yellowing (data not shown) as seen in the tomato leaves. Thus, rice plants are non-hosts to the bacteria. As Arabidopsis thaliana has been used extensively as a plant host model for several pathogens, we tested B. thailandensis and B. pseudomallei infection in Arabidopsis plantlets via the roots. The average disease scores were maintained at 1 and increased only slightly at days 6 and 7 and were identical for both B. thailandensis and B. pseudomallei infection (Fig &#8203;(Fig5B5B).

Discussion
B. cepacia, the important opportunistic pathogen often associated with cystic fibrosis and chronic granulomatous disease patients [21], was originally described as a phytopathogen causing soft rot in onions [22]. Subsequently, many strains from various B. cepacia complex were shown to be able to cause disease in the alfalfa infection model as well as in the rat agar bead model [23]. In this study, we show that B. pseudomallei and B. thailandensis are also potential plant pathogens. They are capable of infecting susceptible plants such as tomato.

Plant pathogenic bacteria have been shown to express a large number of T3SS effectors capable of interfering with plant basal defense triggered by bacterial pathogen-associated molecular patterns (PAMPs) as well as Resistance (R) protein-mediated immunity typically characterized by the Hypersensitive Response (HR) [24-26]. The outcome of the interaction with susceptible hosts for these successful pathogens would be disease. We found that the virulence of B. pseudomallei in tomato is contributed significantly by T3SS1 and T3SS2, but to a much lesser extent by T3SS3. T3SS1 and T3SS2 are likely non-redundant to each other in causing disease because each mutant demonstrates significant attenuation, possibly because both T3SS1 and T3SS2 are co-ordinately involved in pathogenesis. This is the first time that a role has been defined for T3SS1 and T3SS2 in B. pseudomallei, showing that they are functional and not simply vestiges of evolution. The role of T3SS3 could be due to its contribution of a structural component or chaperone to the other two T3SS or an effector which could also interfere with plant cell physiology albeit less efficiently than with mammalian cells. Nevertheless, our study shows the important role played by T3SS in B. pseudomallei pathogenesis in tomato plants.

In contrast to tomato, we found that both B. pseudomallei and B. thailandensis are non-adapted for rice. This is not surprising as B. pseudomallei are routinely recovered from rice paddy fields in regions of endemicity such as Thailand and have never been reported to cause any disease in rice plants. It is possible that PAMPs from B. pseudomallei and B. thailandensis are able to trigger an effective basal defence from rice to halt bacterial colonization, a common means of plant resistance against non-adapted microorganisms [24-26]. Another intriguing possibility is that compounds secreted by rice plants may inhibit the growth of B. thailandensis and B. pseudomallei. The presence of secondary metabolites induced by B. pseudomallei infection in plants with differential susceptibility to disease could reveal novel anti-infective compounds against melioidosis to counter the problem of extensive antibiotic resistance in this bacterium.

Thus, B. pseudomallei joins a growing list of human pathogens which have been found to be able to infect plants [27], the first of which to be described was P. aeruginosa [28]. The plant host model has been used to perform large scale screening of a library of P. aeruginosa mutants to identify novel virulence factors [29] as some virulence factors encoded by genes such as toxA, plcS and gacA were shown to be important for bacterial pathogenesis in both plants and animals [6]. Given the evidence that B. pseudomallei T3SS3 may be capable of interacting with both mammalian and plant hosts, and the ability of B. pseudomallei to infect tomato, one could develop susceptible plants as alternative host models for large scale screening of B. pseudomallei mutants to aid in novel virulence factor discovery, similar to what had been done for P. aeruginosa.

Previously, B. pseudomallei has been shown to infect C. elegans [30] and Acanthamoeba species [31] and C. elegans could be used as an alternative host model for large scale screening and identification of B. pseudomallei virulence factors [30]. Our current finding reveals the additional versatility of B. pseudomallei as a pathogen and further research would likely uncover novel bacterial mechanisms capable of interacting with its varied hosts. Much more work is needed to define the susceptibility of various plant species to B. pseudomallei to find a suitable plant host for virulence factor discovery. It remains to be seen if B. pseudomallei is a natural pathogen for crops such as tomatoes.

Conclusions
In summary, we identified B. pseudomallei as a plant pathogen capable of causing disease in tomato but not rice plants. B. pseudomallei T3SS1 and T3SS2 contribute significantly to disease whereas T3SS3 plays a more minor role. Although the significance of B. pseudomallei as a natural plant pathogen in the environment is unknown, one could postulate that certain plants may serve as a reservoir for the bacteria. Since B. pseudomallei is classified as a bioterrorism agent by the US Centers for Disease Control and Prevention http://www.cdc.gov/od/sap, our findings indicate that it may be necessary to re-evaluate whether B. pseudomallei poses threats beyond the animal kingdom and whether plant systems could be used as environmental indicators of the presence of the bacteria either as endemic residents or due to the intentional release by terrorists, a concept that has been previously proposed [27].
 
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This touches upon several things; metabolic syndrome, diet, genetic influences, and a hygiene hypothesis basis for inflammatory immune dysfunction:

http://www.nytimes.com/2012/08/26/opinion/sunday/immune-disorders-and-autism.html?pagewanted=all
Very interesting article indeed.
Thank you.

The link between diseases from the mother and autism in a child is interesting.
That makes me wonder about something :
Especially because some of these diseases are labeled as auto immune diseases. These "auto immune" diseases may very well have an epigenetic history. Thus these diseases are seen as having a genetic component. But how the disease became a hereditary disease... With the exclusions of some diseases (gene copy errors ?), epigenetics might play a very large role in hereditary auto immunity ?

Some excerpts :

So here&#8217;s the short of it: At least a subset of autism &#8212; perhaps one-third, and very likely more &#8212; looks like a type of inflammatory disease. And it begins in the womb.

It starts with what scientists call immune dysregulation. Ideally, your immune system should operate like an enlightened action hero, meting out inflammation precisely, accurately and with deadly force when necessary, but then quickly returning to a Zen-like calm. Doing so requires an optimal balance of pro- and anti-inflammatory muscle.
In autistic individuals, the immune system fails at this balancing act. Inflammatory signals dominate. Anti-inflammatory ones are inadequate. A state of chronic activation prevails. And the more skewed toward inflammation, the more acute the autistic symptoms.
Nowhere are the consequences of this dysregulation more evident than in the autistic brain. Spidery cells that help maintain neurons &#8212; called astroglia and microglia &#8212; are enlarged from chronic activation. Pro-inflammatory signaling molecules abound. Genes involved in inflammation are switched on.
These findings are important for many reasons, but perhaps the most noteworthy is that they provide evidence of an abnormal, continuing biological process. That means that there is finally a therapeutic target for a disorder defined by behavioral criteria like social impairments, difficulty communicating and repetitive behaviors.

But how to address it, and where to begin? That question has led scientists to the womb. A population-wide study from Denmark spanning two decades of births indicates that infection during pregnancy increases the risk of autism in the child. Hospitalization for a viral infection, like the flu, during the first trimester of pregnancy triples the odds. Bacterial infection, including of the urinary tract, during the second trimester increases chances by 40 percent.
The lesson here isn&#8217;t necessarily that viruses and bacteria directly damage the fetus. Rather, the mother&#8217;s attempt to repel invaders &#8212; her inflammatory response &#8212; seems at fault. Research by Paul Patterson, an expert in neuroimmunity at Caltech, demonstrates this important principle. Inflaming pregnant mice artificially &#8212; without a living infective agent &#8212; prompts behavioral problems in the young. In this model, autism results from collateral damage. It&#8217;s an unintended consequence of self-defense during pregnancy.
Yet to blame infections for the autism epidemic is folly. First, in the broadest sense, the epidemiology doesn&#8217;t jibe. Leo Kanner first described infantile autism in 1943. Diagnoses have increased tenfold, although a careful assessment suggests that the true increase in incidences is less than half that. But in that same period, viral and bacterial infections have generally declined. By many measures, we&#8217;re more infection-free than ever before in human history.

Better clues to the causes of the autism phenomenon come from parallel &#8220;epidemics.&#8221; The prevalence of inflammatory diseases in general has increased significantly in the past 60 years. As a group, they include asthma, now estimated to affect 1 in 10 children &#8212; at least double the prevalence of 1980 &#8212; and autoimmune disorders, which afflict 1 in 20.

Both are linked to autism, especially in the mother. One large Danish study, which included nearly 700,000 births over a decade, found that a mother&#8217;s rheumatoid arthritis, a degenerative disease of the joints, elevated a child&#8217;s risk of autism by 80 percent. Her celiac disease, an inflammatory disease prompted by proteins in wheat and other grains, increased it 350 percent. Genetic studies tell a similar tale. Gene variants associated with autoimmune disease &#8212; genes of the immune system &#8212; also increase the risk of autism, especially when they occur in the mother.

In some cases, scientists even see a misguided immune response in action. Mothers of autistic children often have unique antibodies that bind to fetal brain proteins. A few years back, scientists at the MIND Institute, a research center for neurodevelopmental disorders at the University of California, Davis, injected these antibodies into pregnant macaques. (Control animals got antibodies from mothers of typical children.) Animals whose mothers received &#8220;autistic&#8221; antibodies displayed repetitive behavior. They had trouble socializing with others in the troop. In this model, autism results from an attack on the developing fetus.

But there are still other paths to the disorder. A mother&#8217;s diagnosis of asthma or allergies during the second trimester of pregnancy increases her child&#8217;s risk of autism.

So does metabolic syndrome, a disorder associated with insulin resistance, obesity and, crucially, low-grade inflammation. The theme here is maternal immune dysregulation. Earlier this year, scientists presented direct evidence of this prenatal imbalance. Amniotic fluid collected from Danish newborns who later developed autism looked mildly inflamed.

Debate swirls around the reality of the autism phenomenon, and rightly so. Diagnostic criteria have changed repeatedly, and awareness has increased. How much &#8212; if any &#8212; of the &#8220;autism epidemic&#8221; is real, how much artifact?

YET when you consider that, as a whole, diseases of immune dysregulation have increased in the past 60 years &#8212; and that these disorders are linked to autism &#8212; the question seems a little moot. The better question is: Why are we so prone to inflammatory disorders? What has happened to the modern immune system?
There&#8217;s a good evolutionary answer to that query, it turns out. Scientists have repeatedly observed that people living in environments that resemble our evolutionary past, full of microbes and parasites, don&#8217;t suffer from inflammatory diseases as frequently as we do.

Generally speaking, autism also follows this pattern. It seems to be less prevalent in the developing world. Usually, epidemiologists fault lack of diagnosis for the apparent absence. A dearth of expertise in the disorder, the argument goes, gives a false impression of scarcity. Yet at least one Western doctor who specializes in autism has explicitly noted that, in a Cambodian population rife with parasites and acute infections, autism was nearly nonexistent.

For autoimmune and allergic diseases linked to autism, meanwhile, the evidence is compelling. In environments that resemble the world of yore, the immune system is much less prone to diseases of dysregulation.

Generally, the scientists working on autism and inflammation aren&#8217;t aware of this &#8212; or if they are, they don&#8217;t let on. But Kevin Becker, a geneticist at the National Institutes of Health, has pointed out that asthma and autism follow similar epidemiological patterns. They&#8217;re both more common in urban areas than rural; firstborns seem to be at greater risk; they disproportionately afflict young boys.
The theory is that the hygiene hypothesis is the problem.
IMHO:
I do not think that that is the complete explanation.
It is one sided exposure to certain pathogens and one sided exposure to toxins. Combine that with an unbalanced one sided diet...
It seems once again that the right balance is much more important.
Having a functioning immune system without auto immunity but a short lifespan because of all these parasites ? Unless the right balance of parasites, fungi, protozoa and bacteria is the key.
Because all these micro organisms also fight each other and keep each other in check. And when they fight for survival and food, our immune system only has to take care of the runaways, the victorious of those fights. Seen form a biological perspective, it works in steps. Like a pyramid. Each section has special function. At least that is what i am wondering about.

Some years back, he began comparing wild sewer rats with clean lab rats. They were, in his words, &#8220;completely different organisms.&#8221; Wild rats tightly controlled inflammation. Not so the lab rats. Why? The wild rodents were rife with parasites. Parasites are famous for limiting inflammation.
One should ask more why the immune system needs to be suppressed ?
Also, rats are animals that live in a very pathogen rich environment.
It makes sense that rats have a more aggressive immune system when compared to humans.

I think the better way is not to ingest food riddled with parasites, but to find out why the immune system has become "supercharged" to be so aggressive generation over generation. Mimicry and antibodies comes to mind as well. if from generation to generation a chronic infection would take place, would then with every succeeding generation of a species... Would then the immune system not increasingly start targeting molecules from the body ? Without calculation, i would say statistically yes.
 
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